Angiotensin-Converting Enzyme

InhibitorAssociated Elevations in Serum Creatinine

Is This a Cause for Concern?
George L. Bakris, MD; Matthew R. Weir, MD
Background: Reducing the actions of the renin-
angiotensin-aldosterone system with angiotensin-
converting enzyme inhibitors (ACEIs) slows nephropa-
thy progression in patients with or without diabetes. Post
hoc analyses of many ACEI-based clinical trials demon-
strate the greatest slowing of renal disease progression
in patients with the greatest degree of renal insuffi-
ciency at study initiation. However, many physicians fail
to use ACEIs or angiotensin receptor blockers in pa-
tients 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 se-
rumcreatinine levels, associated with ACEI or angioten-
sin receptor blocker use, results in long-termprotection
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, andplacebo controlled, with
the remainder being smaller randomized studies with a
minimum 2-year follow-up on renal function. These in-
vestigations evaluated patients with and without diabe-
tes or systolic heart failure. Average duration of fol-
low-up for all studies was 3 years. Trials were examined
in the context of changes in either serum creatinine lev-
els or GFR in the group randomized to 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.
Results: Most trials demonstrated that patients with pre-
existing renal insufficiency manifested an acute fall in
GFR, a rise in serumcreatinine, or both. Those random-
ized to an ACEI with a serum creatinine level of 124
mol/L or greater (1.4 mg/dL) demonstrated a 55% to
75% risk reduction in renal disease progression com-
pared with those with normal renal function random-
ized to an ACEI. An inverse correlation was observed be-
tween the amount of renal function loss at baseline and
the subsequent rate of annual decline in renal function
following randomization to an antihypertensive regi-
men 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 mol/L (1.4 mg/dL). Thus, with-
drawal of an ACEI in such patients should occur only
when the rise in creatinine exceeds 30% above base-
line 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
T
HE SIXTHREPORTof the Joint
Nat i onal Commi t t ee
(JNC VI) states that there
are specific indications for
angiotensin-converting en-
zyme inhibitor (ACEI) use as part of a regi-
men to lower blood pressure to levels less
than 130/85 mm Hg in patients with dia-
betes mellitus.
1
Moreover, ACEIs should
also be part of the antihypertensive cock-
tail used to achieve this same lower level
of blood pressure reduction in individu-
als withrenal insufficiency.
1
However, data
from the Third National Health and Nu-
trition Examination Survey III (NHANES
III) demonstrate that only half of the 53%
of hypertensive patients treated actually
achieve the bloodpressure goal of less than
140/90 mm Hg.
1
From these data, it is es-
timated 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 in-
sufficiency 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
ORIGINAL INVESTIGATION
From the Rush University
Hypertension/Clinical Research
Center, Department of
Preventive Medicine, Rush
PresbyterianSt Lukes Medical
Center, Chicago, Ill
(Dr Bakris), and Division of
Nephrology, Department
of Medicine, University of
Maryland Medical Center,
Baltimore (Dr Weir).
ARCH INTERN MED/ VOL 160, MAR 13, 2000 WWW.ARCHINTERNMED.COM
685
2000 American Medical Association. All rights reserved.
failure to achieve adequate blood pressure control halted
the previously observed trend in reduction of cardio-
vascular mortality and subsequently increased morbid-
ity frommyocardial infarction, heart failure, stroke, and
renal disease.
1
Another group that may require reductions in ar-
terial pressure to less than 130/85 mm Hg to slow the
rate of renal disease progression are African Ameri-
cans.
3,4
Many such patients experience a transient rise in
serum creatinine levels after treatment with an ACEI or
angiotensinreceptor blocker (ARB) is startedor after blood
pressure is adequately reduced. A rise in the serum cre-
atinine level consequently leads to physician reticence
to stay the course with a given therapy. This action sub-
sequently results in failure to maintain adequate blood
pressure goals. Thus, some patients are deprivedof known
strategies that delay progression of renal disease.
It is noteworthy that clinical trials in both heart fail-
ure and progression of renal disease support the concept
that ACEIs reduce cardiovascular mortality and renal dis-
ease 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
types of patients. Despite these trial outcomes, lower doses
of ACEIs are used in everyday practice, a trend not ex-
plainable by data fromclinical trials. It likely reflects, how-
ever, concern about safety and tolerability of higher ACEI
doses. Physicians shouldbe aware that at these lower doses,
ACEIs might not provide the same positive outcomes in
preservationof renal functionas notedinclinical trials. This
reduced benefit from lower doses of ACEIs may relate to
either a failure of blood pressure control or the relative de-
gree of ACE inhibition itself.
Some of the main reasons for the failure to achieve
adequate drug dosing relate toemotion-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
Dose-
related changes in serum creatinine and potassium levels
dooccur withACEIs, however, andare predictable inmany
cases. These ACEI-associated changes may serve to be di-
agnostic as well as therapeutic. However, many physi-
cians, including nephrologists, view a rise in serum cre-
atinine level as a contraindication for ACEI use.
The most common cause of an acute rise in serum
creatinine level, following inhibition of the renin angio-
tensin system (RAS), results from a decreased effective
arterial blood volume. This is due to hypoperfusion sec-
ondary to volume depletion from overaggressive diure-
sis, 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 hemody-
namic effect is a loss of the kidneys ability to autoregu-
late pressure through the nephron.
22-24
Consequently,
there is a direct relationship between blood pressure and
GFR, whereas under normal circumstances there is a sig-
moidal relationship. This is discussed later in this ar-
ticle. 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 promi-
nent in persons with a long history of markedly el-
evated blood pressure and renal insufficiency.
25
Last, bilateral renal artery stenosis might also be a
cause of elevated serum creatinine levels following ini-
tiation of ACEI therapy. It occurs, however, with a much
lower frequency andshouldbe consideredinpatients with
extensive atherosclerotic cardiovascular disease or who
smoke. It should also be considered in individuals in
whom rehydration has not stabilized or serum creati-
nine reduced toward normality within a fewweeks. Fac-
tors to consider when an acute rise in serum creatinine
level is observed are
decreasedeffectivecirculatingvolume(most common);
advanced age (65 years) with and without preexist-
ing lipid abnormalities; and
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 evalua-
tion met the following criteria: (1) were random-
ized to either ACEI-based therapy or blood pressure
control using an ACEI as part of the therapeutic ar-
mamentarium; (2) had a minimum follow-up pe-
riod 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 pres-
sure goals of less than 140/90 mm Hg.
Twelve randomized clinical trials met these
criteria. Six of these studies were multicenter, double-
blinded, 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 progressionamong pa-
tients with and without diabetes or systolic heart fail-
ure. Mean SD duration of follow-up for all studies
was 3.2 0.3 years. Trials were examined in the con-
text of changes ineither serumcreatinine 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 pe-
riods of less than6 months and at trial end, were used.
If serum creatinine values were not available, then
GFR data are reported. Trends in the changes of se-
rum creatinine values or GFR are reported. In addi-
tion, changes in serum potassium values were as-
sessed at baseline and study end. These are reviewed
in the context of changes in renal function.
ARCH INTERN MED/ VOL 160, MAR 13, 2000 WWW.ARCHINTERNMED.COM
686
2000 American Medical Association. All rights reserved.
baseline serumcreatinine level of 124 mol/Lor 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 mmHg when
previously elevated to levels greater than 180/110
mm Hg for long periods of time.
Inhibition of the RAS blunts the maximal capaci-
tance 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 con-
cept that a reduction in heart rate, by -blockers,
reduces the incidence of cardiovascular events. Thus,
we argue that an initial, limited, rise in serum creati-
nine level is beneficial within the context of preserving
renal function.
RESULTS
GENERAL TRENDS
The clinical studies reviewed indicate that a limited el-
evation in serum creatinine, ie, 30% or less above base-
line, following initiation of therapy with an ACEI or ARB
was seeninpatients withrenal 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). Assum-
ing normal volume and sodiumintake, a rise inserumcre-
atinine that follows ACEI or ARB therapy should stabi-
lize within2to4weeks (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
beenadequately controlled, the probability of anacute rise
in serum creatinine level following this period is un-
likely. There are 3 exceptions to this statement: (1) ini-
tiation 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) develop-
ment of volume depletionfromnondiuretic-inducedcauses
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 regard-
less 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 espe-
cially true for diabetic nephropathy. The effects of ACEIs
on serumcreatinine values and renal function fromclini-
cal trials in patients with renal insufficiency are summa-
rized in the Table.
Tworepresentative, long-termstudies inpatients with
diabetic nephropathy illustrate that the initial reduction
in GFR, following initiation of ACE inhibition, reverted
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
receivedACEIs for anaverage periodof 6years. Inthe ACEI
group there was a clear initial reduction in GFR by 3%to
9%belowbaseline at this time. Overall, meanarterial pres-
sure ranged from105 to 109 mmHg. 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 treat-
ment andclonidine was substitutedtomaintainbloodpres-
sure control. The GFRreturnedto levels not different from
baseline within1monthof ACEI termination, despite simi-
lar 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 ACEI-
associated declines in GFR are reversible and partially in-
dependent 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 pres-
sure. This is because ACEIs lower proteinuria and mark-
edly 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
More-
over, 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).
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)
Baseline 1 2 3 4
Weeks
C
r
e
a
t
i
n
i
n
e
,

m
o
l
/
L

(
m
g
/
d
L
)
A
B
C
ACEI or ARB
Started
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).
ARCH INTERN MED/ VOL 160, MAR 13, 2000 WWW.ARCHINTERNMED.COM
687
2000 American Medical Association. All rights reserved.
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 sub-
jects. 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
persons with serum creatinine values up to 265 mol/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 pro-
found 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
Long-term Outcome of Renal Function in Clinical Trials in Persons With Renal Disease: Impact of ACEI Therapy*
Study N
Duration of
Follow-up, y
Achieved
MAP, mm Hg
Renal Function
6 mo Trial End
Diabetic subjects
Captopril Trial
27
207 3 105 ? 0.15 (Cr clear)
Bakris et al
8
18 5 98 9.47 (GFR) 0.02 (Cr clear)
Lebovitz et al
13
28 3 104 ? 6.3 (GFR)
Nielsen et al
28
21 3 112 3.97 (GFR) 7.1 (GFR)
Bjorck et al
16
40 2.2 102 3.8 (GFR) 2.0 (GFR)
Nondiabetic subjects
AIPRI Trial
29
300 3 100 +26 (Cr) +31 (Cr)
REIN Trial
10
78 3.5 106 ? 6.3 (GFR)
Zucchelli et al
17
32 3 100 ? 0.04 (Cr Clear)
Hannedouche et al
14
52 3 105 ? 4.8 (GFR)
MDRD Trial
25
255 3 105 5.7 (GFR) 3.8 (GFR)
94 14.4 (GFR) 2.9 (GFR)
Ihle et al
19
36 2 101 0.42 (GFR) 0.7 (GFR)
Kamper et al
18
35 2.2 99 3 (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.
125
115
105
95
Baseline 1 mo 6 y 1 mo Off ACEI
+ Clonidine
B
P
,

m
m

H
g

90
85
80
75
70
65
60
Baseline 1 mo 6 y 1 mo Off ACEI
+ Clonidine
G
F
R
,

m
L
/
m
i
n

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.
ARCH INTERN MED/ VOL 160, MAR 13, 2000 WWW.ARCHINTERNMED.COM
688
2000 American Medical Association. All rights reserved.
serum creatinine level is as low as 141 mol/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
mol/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 mol/L (1.0 mg/dL),
and similar degrees of blood pressure reduction with
the ACEI, experienced only a 4% risk reduction in dou-
bling of serum creatinine or incidence of death, dialysis,
or transplantation.
Seven separate trials have examined the natural
history of renal disease among patients with nondia-
betic renal insufficiency, with a range of serum creati-
nine values between 133 and 265 mol/L (1.5-3.0
mg/dL) (GFR range, 17-55 mL/min) (Table). Patients
in these trials were randomized to receive antihyper-
tensive therapy that contained either placebo or an
ACEI to achieve blood pressure control. In the
Angiotensin-Converting Enzyme Inhibition in Pro-
gressive Renal Insufficiency (AIPRI) trial,
29
patients
with a serum creatinine level greater than 177 mol/L
(2.0 mg/dL) had a 66% risk reduction in renal dis-
ease progression. This in contrast to those with a
serum creatinine level less than 177 mol/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
177 mol/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 fromprevious trials,
support the concept of a bell-shaped curve with regard
to the acute effects of ACE inhibition on serum creati-
nine levels. That is, at normal levels of serum creatinine
there is little to no effect on the change in serum creati-
nine 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 hyper-
kalemia 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 con-
comitant use of nonsteriodal anti-inflammatory agents
and/or reduced potassium clearance secondary to re-
duced 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 lev-
els that follow ACEI initiation limit the use of ACEI in
most patients with concomitant renal or cardiac dis-
ease. A case-controlled study of outpatients followed
6
4
2
0
8
10
12
14
16
0-250 250-1000 1000-3000
Proteinuria, mg/d

G
F
R
,

m
L
/
m
i
n
Initial GFR (<92 mm Hg MAP)
Final GFR (<92 mm Hg MAP)

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.
120
100
80
60
40
20
0 354
(4)
442
(5)
530
(6)
265
(3)
177
(2)
88
(1)
619
(7)
707
(8)
796
(9)
Serum Creatinine, mol/L (mg/dL)
G
F
R
,

m
L
/
m
i
n
Dialysis
A
C
E
I

B
e
n
e
f
i
t
(
B
a
s
e
d

o
n

G
F
R
)
ACEI Benefit
(Based on Serum
Creatinine Level)
General Population
Age >65 y or Weight <49.5 kg
Lab Abnormalities of Renal Failure Start
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 mol/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.
ARCH INTERN MED/ VOL 160, MAR 13, 2000 WWW.ARCHINTERNMED.COM
689
2000 American Medical Association. All rights reserved.
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 potas-
sium 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 pre-
dicting hyperkalemia was a baseline serum creatinine
level of 144 mol/L (1.6 mg/dL) or greater. Other fac-
tors 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 nondia-
betic renal disease (serum creatinine levels, 133-265
mol/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 hydro-
chloride 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 devel-
opment of either functional renal insufficiency or
hyperkalemia between an ACEI, captopril, or an ARB,
losartan potassium.
15
The incidence of persisting func-
tional 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 ob-
served this lower incidence of hyperkalemia with use of
angiotensin receptor antagonists.
37,38
These studies evalu-
ated the effects of ACEIs and ARBs on potassium bal-
ance and the RAS among patients with renal insuffi-
ciency; 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 from0.05 to 0.3 mmol/L;
the average increase when given an ACEI was approxi-
mately 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 specifi-
cally indicated for use in patients with renal insuffi-
ciency by the JNC VI.
1
They have proven therapeutic
benefits, particularly in patients with renal insufficiency
(ie, serum creatinine level 133-265 mol/L [1.5-3.0
mg/dL]). This class of drugs may also provide renopro-
tective effects that are nonblood 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 ben-
efits 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 mol/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. Inhi-
bition 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 insuffi-
ciency, however, fewer functional nephrons, remnant
0 1 2 3 4 5 6 7
Relative Risk
Concomitant Use of Diuretics
Serum Creatinine
>133 mol/L
(>1.5 mg/dL)
Long-Acting ACEIs
Heart Failure
Serum Creatinine
<133 mol/L
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
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690
2000 American Medical Association. All rights reserved.
nephrons, are present and thus function at a relatively
higher baseline pressure to maintain stable renal func-
tion.
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 likeli-
hood 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 pres-
sure 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 autoregula-
tory ability preserved by the kidney. If autoregulation
is not present, then the GFR will change in direct rela-
tion 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 inhibi-
tors blunt the rise in renal blood flow and GFR that fol-
low 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 neph-
ron 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 glomeru-
lar 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 mod-
els of renal insufficiency and in people with renal dys-
function following protein loading.
45-48
The blunted
rise in GFR, in part, secondary to persistent efferent
arteriolar dilation that results from decreased angio-
tensin II effects, thus inhibits one mechanism by
which the nephron compensates to heightened urea
loads. This is analogous to the -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 organs response to a heightened work demand.
This assertion is based on the observation that these
classes of agents have been shown to reduce cardiovas-
cular mortality.
5-7
A simple way to conceptualize the benefits of
ACEIs to the kidney is through an analogy with car-
diac function. We propose that ACEIs reduce the
maximal response of a given nephron to excrete meta-
bolic waste products by reducing its baseline GFR.
This is analogous to the effects of -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 associ-
ated with a reduction in cardiac mortality in secondary
prevention trials.
49
When -blocker therapy is stopped,
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 concept
9,10
(Table).
Angiotensin-converting enzyme inhibitors also
affect the morphology of the heart, kidney, and vascu-
lature over time. They are known to have antifibro-
genic effects on various organs including the vascula-
ture and thereby help to preserve organ function.
50-52
Their effects are secondary to inhibition of various
cytokines including transforming growth factor ,
collagen IV, and others.
51
Thus, these agents may
provide additional protection against renal and
cardiovascular disease progression by mechanisms
independent of their blood pressurelowering effects.
This is exemplified by restoration of endothelial func-
tion 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. More-
over, data from clinical trials in both diabetic and non-
diabetic 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 sug-
gested 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
150
140
130
120
110
100
90
80
70
60
50
0 100
% Effect
G
F
R

(
m
L
/
m
i
n
)

o
r

H
R

(
b
e
a
t
s
/
m
i
n
)
GFR Response to
Protein LoadNormal
Reduced
Baseline
Reduced
Baseline
GFR Response to
Protein LoadACEI
HR Response to
ExerciseNormal
HR Response to
Exercise-Blockers
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).
ARCH INTERN MED/ VOL 160, MAR 13, 2000 WWW.ARCHINTERNMED.COM
691
2000 American Medical Association. All rights reserved.
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, trandol-
april or fosinopril), or its discontinuance. This is par-
ticularly true for patients with New York Heart Associa-
tion class IV heart failure.
20,53
Accepted for publication May 27, 1999.
Reprints: George Bakris, MD, Rush PresbyterianSt
Lukes Medical Center, Department of Preventive Medi-
cine, 1700 Van Buren St, Suite 470, Chicago, IL 60612
(e-mail: gbakris@rush.edu).
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ACEI Started
B Serum Creatinine Increased
<30%
No Electrolyte Issues
A Serum Creatinine
Unchanged
Continue to Titrate Agent Until
BP in Goal

Recheck Electrolytes and

Serum Creatinine (3-4 wk)
If Stable, Recheck Annually;
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BP in Goal
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2-3 wk
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Level
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BP in Goal
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<30% Increase in Creatinine +
BP

If Not in GoalAdd Other

Agents to Achieve BP Goal
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3-4 wk
If BP in Goal, Proceed as
per A, If >30% Rise See

C Serum Creatinine +
Increased 50%
Check Electrolytes and
Serum Creatinine
(1-2 wk)
Exclude Hypoperfusion States
(Volume Depletion and NSAID
Use)
Captopril Renal Scan or
Angiogram to Rule Out
Bilateral Renal Artery Stenosis
Figure 7. A schematic approach to a patient with renal insufficiency started on therapy with an angiotensin-converting enzyme inhibitor (ACEI). Asterisk indicates blood
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hypoperfusion are eliminated, and nonsteroidal anti-inflammatory drugs (NSAIDs) are not given, treat as if bilateral renal arterial disease is present.
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