Open Journal of Nephrology, 2013, 3, 128-134 Published Online September 2013 (
Antihypertensive Therapy in Non-Diabetic Chronic Kidney
Disease Associated with Proteinuria in Adults
Khawar Maqsood1, Adeel Siddiqui2, Geoffrey Teehan2*
1Department of Medicine, Baystate Medical Center, Tufts University School of Medicine, Springfield, USA
2Department of Nephrology, Lankenau Medical Center, Lankenau Institute for Medical Research, Wynnewood, USA
Email: *
Received July 3, 2013; revised August 4, 2013; accepted August 14, 2013
Copyright © 2013 Khawar Maqsood et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Controlling blood pressure and reducing proteinuria are common goals in Chronic Kidney Disease associated with hy-
pertension and proteinuria and lead to fewer cardiovascular outcomes. This rev iew summarizes the available literature.
Keywords: Hypertension; Proteinuria; Chronic Kidney Disease
1. Introduction
Proteinuria is a risk factor for progression of chronic kid-
ney disease (CKD) and is associated with adverse cardio-
vascular outcomes. Controlling blood pressure particu-
larly with strongly anti-proteinuric agents slows the pro-
gression of chronic kidney disease (CKD) and delays/
prevents cardiovascular outcomes. Angiotensin convert-
ing enzyme inhibitors (ACE-I) and angiotensin receptor
antagonists (ARBs) have a blood pressure-independent
antiproteinuric effect and are considered first line agents
in this scenario [1]. This review will app rise th e literatu re
to date on an tihyp erten s ive agents studied in non-d iabetic
proteinuric kidney disease. Table 1 summarizes these
2. ACE Inhibitors
Captopril was the first ACE-I approved by Food and
Drug Administration (FDA) in 1981 followed by enala-
pril which was marketed two years later. Since then at
least twelve other ACE-I have been marketed. Multiple
trials have identified a preferential benefit of ACE-I in
reducing proteinuria when compared with other anti-
hypertensive drugs. The basis of all these studies was the
observation that protein excretion varies directly with the
intra-glomerular pressure in animals with structural glo-
merular disease [2].
Apart from the reduction in intra-glomerular pressure,
a variety of other mechanisms may contribute to ACE-I
induced reduction in proteinuria. These include:
The hemodynamic effects of ACE inhibition occur
rapidly but then become stable, whereas protein ex-
cretion progressively decreases over weeks to several
months [3].
Acute administration of angiotensin II increases intra-
glomerular pressure by causing renal and systemic
vasoconstriction but does not reverse the antiprotein-
uric effect of ACE-I [4].
Nephrin is a major component of the podocyte slit
pore membrane and an important contributor to the
glomerular filtration barrier. Angiotensin II reduces
the expression of nephrin [5]. In contrast, ACE-I in-
crease expression of nephrin [6].
ACE-I may contribute to slowing of renal disease by
their possible anti fibrotic properties.
ACE-I related reduction in proteinuria may be associ-
ated with a reduction in serum lipid level which may
have a beneficial effect on progression of renal dis-
ease and systemic atherosclerosis.
Multiple clinical trials have demonstrated a beneficial
effect of antihypertensive therapy with renin-angiotensin
system (RAS) inhibitors, mostly ACE-I in patients with
proteinuric non-diabetic chronic kidney disease (CKD).
Jafar et al studied 1860 patients with CKD in 11 ran-
domized controlled trials (RCT) and the response to
ACE-I versus other antihypertensives or placebo [7].
ACE-I use was associated with significant reductions in
the rate of progr ession to end-stage renal disease (ESRD)
(7.4% versus 11.6%, RR 0.69, 95% CI 0.51 - 0.94),
while that for doubling of the baseline serum creatinine
concentration or ESRD was 13.2 versus 20.5 percent (RR
0.70, 95% CI 0.55 - 0.88) independent of blood pressure
*Corresponding author.
opyright © 2013 SciRes. OJNeph
Table 1. Studies of antihypertensive treatment in patients with chronic kidney disease.
Study Design/Intervention Effect on GFR Effect on Protein uriaCardiovascular
outcomes Others
Maione et al9
SR of 85 RCT. 21,708
patients. ACE-I, ARBs and
combination therapy in
patients with albuminuria
and other cardiovascular
risk factors.
ACE-I better than
placebo. ARB
better than placebo.
not better than
ACE-I better
than placebo.
ARB better
than placebo.
Combination not
better than
Better with
ACE-I versus
placebo only. N/A
Benazepril trial10
583 patients, 300 patients
received benazepril and
283 received placebo.
Primary end po int: dou bling
of the baseline Cr or the
need for HD.
Benazepril better
than placebo for
primary end point.
Benazepril therapy
reduced protein
excretion by 25
percent compared
with placebo.
Outcomes better
in patients with
diseases, diabetic
and those with
baseline urinary
protein excretion
>1 g/24 hr.
REIN trial11
Prospective double-blind
trial, 352 patients were
classified according to
baseline proteinuria
1 - 3 g/24 h
> 3 g/24 h
Randomly assigned t o
ramipril or placebo plus
conventional antihypertensive
therapy targeted at achieving
diastolic blood pressure
under 90 mm Hg.
Primary end point:
rate of GFR decline.
Significantly lower
rate of GFR decline
with ramipril.
In patients with
baseline proteinuria
of 3 g/24 h or higher,
ramipril was more
Reno protective than
N/A More benefits
seen with higher
REIN-2 trial13
Multicenter RCT, 338 patients
on ramipri l were randomized
to intensified control with
felodipine vs conventional
blood pressure control.
Primary ou tc ome was
progression to ESR D .
No benefit seen with
intensified BP control
with felodipine. N/A N/A
No Reno protection
in patients with
proteinuric renal
disease with
calcium channel
AASK trial14
1094 African American
patients with hypertensive
renal disease. Randomly
assigned to ramipril,
amlodipine or m etoprolol
Primary outcome: rate
of change in GFR.
Secondary outcome:
composite endpoint of r
eduction in GFR of more
than 50% or more than
25 mL/min per 1.73 m 2;
ESRD; or death.
At 3 years, ramipril
significantly reduced
the relative risk of the
composite endpoint but
not primary o utco me.
Beneficial effect of
ramipril was seen in
patients with urine
protein-to-Cr ratio >0.22
(300 mg prote i n/ 24 hr).
Ramipril sho w e d
enefit in patients
with urine
ratio >0.22.
ACE-I and ARB combination
versus monotherapy.
5623 patients with estimated
GFR less than 60 mL/min per
1.73 m2 and/or proteinuria.
ACE + ARB resulted
in a small but significant
increase in the incidence
of ESRD and a non
significant increase in
ESRD alone.
N/A Combination
therapy not better
than monotherapy.
Higher potassium
level with
Abbreviations: SR systematic review, RCT randomized controlled trial, ACE-I angiotensin converting enzyme inhibitor, ARB angiotensin receptor bl ocker, Cr
creatinine, GFR glomerular filtration rate, HD hemodialysis
Copyright © 2013 SciRes. OJNeph
control. These benefits of ACE-I correlated with increas-
ing baseline proteinuria but did not apply to those with
proteinuria below 500 to 1000 mg/day [8].
Maione et al. conducted a systematic review of 85
RCTs (21,708 subjects) to look at ACE-I, ARBs and
combination therapy in patients with microalbuminuria,
macroalbuminuria and other cardiovascular risk factors
[9]. Neither ACE I, ARB, nor the combination of the two
was associated with a significant reduction in the risk of
all-cause morta lity or fatal card iac-cerebrovascular events.
ACE I, and not ARB, did however reduce the risk of
nonfatal cardiovascular events. Development of ESRD
disease and progression of microalbuminuria to macro-
albuminuria were reduced significantly with ACE-I ver-
sus placebo, ARB versus placebo but not with combined
therapy with ACE-I and ARB versus monotherapy. Au-
thors concluded that ACE-I and ARB exert independent
renal and nonfatal cardiovascular benefits while their
effects on mortality and fatal cardiovascular disease are
uncertain. Use of combination therap y was not supported
by the evidence.
Maschio et al. performed a placebo-controlled RCT
involving 583 patients with renal insufficiency (crea-
tinine clearance 30 - 60 ml per minute) in which 300 pa-
tients received benazepril and 283 received placebo. The
primary end point was a doubling of the baseline serum
creatinine concentration or the n eed for dialysis. At three
years the risk reduction attributed to benazepril was 53
percent overall (95% CI, 27% - 70%) and was particu-
larly evident in milder k idney disease. The risk reduction
was greatest among men; those with glomerular diseases,
diabetic nephropathy, or miscellaneous or unknown cau-
ses of renal disease; and those with baseline urinary pro-
tein excretion above 1 g per 24 hours. Benazepril was not
effective in patients with polycystic kidney disease [10].
The Ramipril Efficacy in Nephropathy (REIN) trial
was a RCT in which patients (N = 352) with proteinuric
non-diabetic CKD were randomized to ramipril or pla-
cebo plus other antihypertensive therapy to attain a dia-
stolic pressure below 90 mmHg. It showed similar bene-
fits as the Maschio trial [11]. Stratified by level of daily
proteinuria, the primary endpoint was the rate of glome-
rular filtration rate (GFR) decline. The trial was termi-
nated prematurely in patients excreting more than 3
grams of protein per day because of a significant benefit
with ACE-I in ameliorating the rate of decline of renal
function (0.53 versus 0.88 mL/min per month for pla-
cebo). Subsequently all pa tients with pr oteinu r ia of 3 g or
more per 24 h either continued on ramipril or were shift-
ed to ramipril.
A REIN follow-up study compared the rate of decline
of renal function and the need for dialysis in patients who
continued to receive ramipril (51 patients) and in those
originally randomized to conventional antihypertensive
therapy plus placebo who were switched to ramipril at
the beginning of the observational follow-up (46 pa-
tients). At 20 months (and at 44 months for the trial
phase and observational follow-up combined), mean rate
of GFR decline slowed significantly and end of trial
GFRs were significantly higher in the ramipril group (36
vs 24 ml per minute, P = 0.01). Progression to ESRD was
more common in those receiving placebo (35 versus 19,
P = 0.027) [12]. The original and follow-up ramipril
studies strongly suggest that patients who particularly
benefit are those with prominent proteinuria, but signifi-
cant benefit was also seen in patients with sub-nephrotic
proteinuria (1.0 to 2.9 g/day).
REIN-2 evaluated lowering blood pressure beyond
usual targets in patients with ch ronic nephropath ies using
ACE I. Patients receiving ACE I (Ramipril 2.5 - 5 mg/d)
with non-diabetic proteinuric CKD (mean baseline GFR
35 mL/min and mean proteinuria 2.9 g/day, N = 338)
were enrolled in this RCT [13]. Subjects were randomly
assigned to either conventional (diastolic < 90 mm Hg; n
= 169) or intensified (systolic/diastolic < 130 /80 mm Hg;
n = 169) blood-pressure control with Felodipine (5 - 10
mg/day) added as needed to achieve the intensified
blood-pressure level. The primary outcome measure,
time to ESRD over 36 months did not differ between the
two groups (20% vs 23%, P = 0.99). Further blood pres-
sure reduction with Felodipine therefore is not warranted
to slow progression to ESRD in this population. These
findings are consistent with previous observations show-
ing that dihydropyridine calcium channel blockers fail to
provide renoprotection in patients with non-diabetic pro-
teinuric renal disease.
Hypertension and ESRD are more prevalent among
African Americans than Caucasians. Monotherapy with a
calcium channel blocker or a diuretic may be superior in
this population than ACE-I. The African American Study
of Kidney Disease and Hypertension (AASK trial) [14]
included 1094 African American patients with hyperten-
sive renal disease. Mean GFR was 46 ml/min (range 20-
65 mL/min per 1.73 m2) and mean protein excretion was
about 600 mg/day in men and 400 mg/day in women.
Patients were randomly assigned to three different anti-
hypertensive drugs and to two different blood pressure
goals. The blood pressure target was a mean arterial pres-
sure of 92 mm Hg or less in the intensive-control group
(corresponds to lower than the traditional blood-pressure
target of 130/80 mm Hg for CKD) and 102 to 107 mm
Hg in the standard-control group (corresponds to the tra-
ditional blood-pressure target of 140/90 mm Hg). Pa-
tients were randomly assigned to treatment with an ACE
inhibitor (ramipril, 2.5 - 10 mg/day), a calcium channel
blocker (amlodipine, 5 - 10 mg/day), or a beta blocker
(metoprolol, 50 - 200 mg day); other antihypertensive
drugs were added to initial monotherapy to achieve the
Copyright © 2013 SciRes. OJNeph
blood pressure goals. The primary outcome was the rate
of change in GFR; the main secondary outcome was a
composite endpoint of: reduction in GFR of more than 50
percent or more than 25 mL/min per 1.73 m2; ESRD; or
Although the GFR decline with ramipril and amlodip-
ine therapy were similar at 3 years, ramipril significantly
reduced the relative risk of the composite endpoint by 38
percent. Additionally, ramipril was significantly better at
slowing GFR decline among those with a urine protein-to
creatinine ratio >0.22 (approximately equivalent to 300
mg protein in 24 hours). It also showed that sustained-
release metoprolol has antiproteinuric effects nearly eq-
ual to that of ramipril (P = 0.06 for the comparison of
total change over 4 years) and better than that of am-
lodipine. Proteinuria increased by 58% for the amlodip-
ine group and declined by 14% in the sustained-release
metoprolol group between baseline and 6 months (P <
0.001) [14].
After completion of the AASK trial, all of the partici-
pants were invited to enroll in a cohort phase during
which ramipril was prescribed to everyone. After an ad-
ditional five years of follow-up progression of neph-
ropathy was significan t ly slowed b ut n ot stoppe d [15].
2.1. Use of ACEI/ARB in Advanced CKD
The pitfalls of using an ACE-I or ARBs in advanced
CKD include an initial GFR decline and hyperkalemia,
prompting many practition ers to avoid their use. Fan Fan
Hou et al. enrolled 422 patients with non-diabetic CKD
and randomly assigned them to benazepril or placebo
plus other antihypertensive therapy to attain a systolic
and diastolic pressure below 130 and 80 mmHg, respec-
tively [16]. Patients were divided into two groups based
on renal function: Group 1 (N = 141, Serum Creatinine
1.5 - 3.0 mg/dL; mean GFR 37 ml/min/1.73 m2, mean
proteinuria 1.6 g/d) and Group 2 (N = 281, Serum
Creatinine 3.1 - 5.0 mg/dL, mean GFR 26 ml/min/1.73m2,
mean proteinuria 1.6 g/d).
After an eight-week run-in period in which they re-
ceived benazepril at 10 mg/day for four weeks 104 pa-
tients remained in Group 1 an d 224 r emained in Group 2.
Group 1 subjects then received benazepril (at 10 mg
twice daily, since it was deemed unethical to administer
placebo), while Group 2 participants were randomly as-
signed to benazepril (10 mg twice daily) or placebo. Ad-
ditional antihypertensive therapy was administered to
attain blood pressure goals. The primary endpoint was
the composite of doubling of the serum creatinine level,
ESRD, or death, while secondary endpoints were change
in proteinuria and rate of progression of the renal disease.
At a mean follow up of 3.4 years, significantly fewer
Group 2 patients (mean GFR of 26 mL/min per 1.73 m2)
treated with benazepril reached the primary endpoint (41
versus 60 percent with placebo), resulting in an overall
risk reduction of 43 percent with active therapy. The
primary endpoint was reached less often in group 1 pa-
tients (22 percent), who had less severe disease and were
all treated with benazepril.
In group 2 doubling of the serum creatinine and rea-
ching ESRD occurred in 51 and 40% fewer patients re-
ceiving Benazepril. Fall in proteinuria (52 versus 20 per-
cent) and a slower rate of decline in GFR (6.8 versus 8.8
mL/min per 1.73 m2 per year) were also noticed. The
benefits with benazepril were independent of blood
pressure. Benazepril conferred substantial renal benefits
in highly selected patients without diabetes who had ad-
vanced renal insufficiency.
The REIN trial confirms the benefit from ACE-I in pa-
tients with advanced CKD. As previously mentioned,
patients with an initial GFR within the lowest group (11
to 33 mL/min/1.73 m2) had a 20 percent decrease in the
rate of decline in GFR and a 33 percent reduction in the
incidence of end - s t age renal disease.
2.2. Use of ACE I in Elderly Patients
The benefits from RAS inhibition in proteinuric CKD
patients older than 70 years are largely unknown. Most
of the above trials did not include such individuals since
older patients with CKD are less likely to have proteinu-
ria. This is confirmed by an analysis of 1190 National
Health and Nutrition Examination Survey (NHANES)
participants who were over age 70 and had CKD, which
was defined as an estimated GFR < 60 mL/min per 1.73
m2 or an albumin-to-creatinine ratio >200 mg/g of creat-
inine (approximately 300 mg/day) [17]. This level of
proteinuria was present in only 13 percent. There is no
evidence of benefit from RAS inhibition in patients with
protein excretion below 500 mg/day. It suggests that the
great majority of patients over age 70 with CKD would
not benefit from RAS inhibition for renal protection and
may have harm from a higher rate of side effects. How-
ever, this does not fully apply on patients excretin g more
than 1 g/day. Treatment of proteinuric individuals over
the age of 70 with CKD remains an area for investiga-
2.3. Combination of ACE Inhibitors and ARBs
A number of small trials have shown that combination
ACE-I and ARB therapy has a greater antiproteinuric
effect than either agent alone. A meta-analysis of 14 tri-
als in non-diabetic renal disease found that combination
therapy produ ced a significant 18% - 25% greater reduc-
tion in proteinuria compared with monotherapy [18].
These trials did not attempt to identify a maximum anti-
proteinuric dose, did not compare combination therapy to
high dose monotherapy, and did not assess renal out-
Copyright © 2013 SciRes. OJNeph
Combination therapy however may have adverse ef-
fects in proteinuric CKD. The ONTARGET trial evalu-
ated combination therapy versus monoth erapy in a sub set
of 5623 patients who, at baseline, had reduced renal
function (defined as an estimated GFR less than 60
mL/min per 1.73 m2) and/or proteinuria [19]. Combina-
tion therapy resulted in a small but significant increase in
the incidence of ESRD or doubling of the serum crea-
tinine (0.79 versus 0.56 percent per year), but a nonsig-
nificant increase in ESRD alone (0.34 versus 0.27 per-
cent per year) and caused more hyperkalemia while fail-
ing to reduce the risk of cardiovascular disease or death
3. Other Antihypertensive Drugs
3.1. Calcium Channel Blockers
Numerous studies suggest that the dihydropyridine cal-
cium antagonists (DCAs) and non-dihydropyridine cal-
cium antagonists (NDCAs) have differential antiprotein-
uric effects. The NDCAs, such as diltiazem and verapa-
mil are generally considered to have significant antipro-
teinuric effects while DCAs, such as amlodipine and
nifedipine either have no effect or cause a small rise in
protein excretion [21].
Bakris et al. systematically reviewed 23 studies of
NDCA versus DCA and found NDCAs decreased mean
proteinuria by 30 percent and DCAs increased proteinu-
ria by 2 percent (95% CI 10% - 54% for the differences
between the two drug classes). Similar observations were
noted when these agents were used in combination with
ACE-I or ARBs: despite similar reductions in blood
pressure, the mean change in proteinuria was minus 39
and plus 2 percent for NDCAs and DCAs, respectively.
They concluded that NDCA and DCAs lower blood
pressure equivalently, but that NDCAs are superior to
DCAs in reducing proteinuria in both diabetic and non-
diabetic kidney disease [21].
3.2. Aldosterone Antagonists
Addition of aldosterone antagonists may provide renal
benefits to proteinuric CKD patients over and above the
inhibition of RAS blockers by virtue of partially elimi-
nating secondary hyperaldosteronism. Navaneethan et al.
performed a meta- analysis of 11 trials in which patients
were treated with an ACE-I and/or ARB plus either spi-
ronolactone (usually 25 mg/day) or placebo and found a
significantly greater reduction in proteinuria in the spi-
ronolactone group (weighted mean difference 800 mg/day,
95% CI 330 - 1270 mg/day). Short-term chang es in GFR
(less than one year of follow-up) were similar with spi-
ronolactone and placebo. However, most of these studies
did not first maximize the dose of the ACE-I or ARB,
and the aldosterone antagonist was associated with an
increased risk of hyperkalemia (relative risk 3.1 in the
meta-analysis) [22]. Longer-term data are lacking in this
3.3. Direct Renin Inhibitors
Aliskiren, being the first oral direct renin inhibitor (DRI)
became available in the United States in March 2007. A
number of studies have evaluated the blood pressure
lowering effect of aliskiren in combination with other
antihypertensive drugs [23-26]. Its novel mechanism of
action, inhibition of catalytic activity of renin, the most
proximal and rate-limiting step in RAS activation, makes
it of particular interest. In the AVOID trial, aliskiren plus
losartan was associated with a 20 percent greater reduc-
tion in proteinuria compared with losartan alone in pa-
tients with type-2 diabetes and nephropathy in the ab-
sence of a significantly greater effect on blood pressure
[27]. However, this effect on proteinuria did not translate
into a clinical benefit.
In the ALTITUDE trial, 8600 patients with type-2 dia-
betes and kidney disease already taking either an ACE-I
or ARB were randomly assigned to additional therapy
with aliskiren or placebo [28]. The trial was terminated
early due to no benefit on the primary cardiovascular and
renal outcomes and the preliminary analysis indicated
that aliskiren therapy produced a higher rate of adverse
events (i.e., non-fatal stroke, hypotension, hyperkalemia)
[29]. Other studies also described an increased risk of
hyperkalemia when aliskiren is combined with ACE-I or
ARB [30]. Thus, aliskiren should not be combined with
ACE-I or ARBs.
3.4. Drugs with Little or No Effect
Other antihypertensive drugs have little or no effect on
protein excretion. As an example, beta blockers, diuretics,
and the alpha-1-blockers (such as prazosin) typically
have a lesser antiproteinuric effect than RAS inhibitors
[31-33]. A meta-analysis showed that ACE-I lowered
protein excretion by 40 percent compared with 16 per-
cent for beta blockers and 14 percent for other non-cal-
cium channel blocker antihypertensive drugs [31]. Me-
thyldopa and Guanfacine, have little effect on protein
4. Conclusion
Proteinuria is associated with adverse renal and cardio-
vascular outcomes. Retarding proteinuria in CKD slows
progression of CKD and can limit some cardiovascular
outcomes. ACE-I and ARBs are the first line agents in
this setting because they have a blood pressure-inde-
pendent antiproteinuric effect and have shown to im-
prove renal and cardiovascular outcomes. If proteinuria
Copyright © 2013 SciRes. OJNeph
is not controlled with ACE-I or ARB, combination ther-
apy is generally discouraged. We recommend the addi-
tion of an NDCA such as diltiazem or verapamil, long
acting metoprolol or a mineralocorticoid antagonist as
the next line agent. Aggressive measures must be taken
to improve blood pressure and reduce proteinuria for
better renal and cardiovascular outcomes.
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