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NDT Advance Access published September 5, 2013

Nephrol Dial Transplant (2013) 0: 111


doi: 10.1093/ndt/gft281

Original Article
Long-term effects of addition of mineralocorticoid receptor
antagonist to angiotensin II receptor blocker in patients with
diabetic nephropathy: a randomized clinical trial
1

Endocrinology and Metabolism Research Center (EMRC), Vali-Asr

Alireza Esteghamati1,

Tehran, Iran and

University of Medical Sciences, Tehran, Iran

Sorour Jarrah ,

Faculty of Pharmacy, Department of Clinical Pharmacy, Tehran

Mostafa Mousavizadeh ,
Seyed Hamid Khoee2
and Manouchehr Nakhjavani1

Keywords: blood pressure control, diabetic nephropathy,


glomerular ltration rate, mineralocorticoid receptor antagonist,
urinary albumin excretion

Correspondence and offprint requests to:


Alireza Esteghamati; E-mail: esteghamati@tums.ac.ir

and 0.001, respectively). SPR/ARB decreased UAE by 46, 72


and 59% after 3, 12 and 18 months, respectively. Compared
with the continuation regimen, SPR/ARB was superior in
UAE reduction (P = 0.017 after 18 months), independent of
BP change. In both groups, eGFR declined signicantly over
the trial course and the decline rate did not differ signicantly
between the two groups.
Conclusions. Addition of SPR to ARB provides added
benets with respect to BP control and proteinuria diminution. These antiproteinuric effects are not accompanied by
prevention of eGFR loss compared with conventional therapy
with ACE/ARB.

A B S T R AC T
Background. Addition of spironolactone (SPR) to angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) might provide antiproteinuric effects
beyond what is gained by either medication alone. This study
was designed to assess the long-term efcacy of SPR/ARB
combination in comparison with the standard ACE/ARB
regimen in diabetic nephropathy.
Methods. In an open-label, parallel-group, single-center, randomized clinical trial (NCT01667614), 136 patients with diabetes and proteinuria, already treated with enalapril and
losartan, were included. In 74 patients, ACE inhibitors were discontinued. After a wash-out period of 2 weeks, 25 mg SPR daily
was initiated. The remainder of the patients (n = 62) received
ACE inhibitors and ARBs as before. Patients were followed
every 3 months for 18 months. During each visit, systolic and
diastolic blood pressure (BP), urinary albumin excretion (UAE),
serum creatinine, estimated glomerular ltration rate (eGFR)
and serum potassium concentrations were determined.
Results. After 18 months, three patients in the SPR/ARB
group developed asymptomatic hyperkalemia. SPR/ARB signicantly reduced both systolic and diastolic BP (P < 0.001

The Author 2013. Published by Oxford University Press on


behalf of ERA-EDTA. All rights reserved.

INTRODUCTION
The burden of diabetic nephropathy is staggeringconsuming
a large proportion of health resources [1, 2]. A recent costof-illness study from Iran revealed that diabetic nephropathy
accounts for 23% of expenditures attributed to diabetes [3].
Hypertension and proteinuria are established risk factors for
progression to advanced stages of kidney disease in diabetic
populations [4]. Interruption of renin-angiotensin system

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Hospital, School of Medicine, Tehran University of Medical Sciences,

Sina Noshad1,

were carried out according to the principles laid down in the


Declaration of Helsinki. The universitys ethics committee also
approved the trial protocol.
Study design
This single-center, open-label, parallel-group, randomized
clinical trial is registered with ClinicalTrials.Gov (registration
number NCT01667614). Using randomization software, eligible
subjects were assigned to either arm of the trial. We hypothesized that the rate of loss to follow-up would be higher in the
SPR/ARB arm. Therefore, an unbalanced randomization
scheme was employed so that the number of allocated participants would be approximately 20% more in SPR/ARB than in
the ACE/ARB arm. In the SPR/ARB arm (n = 74), enalapril was
discontinued, and after a 2-week wash-out period of ACE
inhibitor, a single-dose of SPR 25 mg daily was added. In the
ACE inhibitor/ARB arm (n = 62), a combination of xed dose
enalapril (3040 mg per day) and losartan (50100 mg per day)
was continued as before. Losartan dosage was comparable
between the trial arms (P = 0.794). No dose adjustment for antihypertensive medications was done during the trial period.
After the baseline visit, regular follow-up visits for both
groups were scheduled 3 months apart. At each visit, physical
examination and laboratory assessments were conducted employing the same protocol (see below). The baseline visit of
SPR/ARB patients was conducted within 1 week of stopping
ACE inhibitor and before initiation of SPR. An extra visit in
the SPR/ARB group was also conducted 1 month after trial
initiation and measurement of serum potassium and an ECG
were done to evaluate asymptomatic hyperkalemia (dened
as potassium concentrations >5.5 meq/L). Before medication
initiation, all of the patients were instructed about the signs
and symptoms of hyperkalemia via an educational leaet.
The patients were also educated regarding the importance of
limiting salt intake and restricting protein consumption to recommended daily amounts in patients with diabetic nephropathy
and/or hypertension. No formal assessment about adherence to
these recommendations was done during the trial.

SUBJECTS AND METHODS

Assessment
Before study commencement, the patients were interviewed
using a pre-designed questionnaire. BP was measured using a
standard mercury sphygmomanometer (Riester, Big Ben
adults, Germany) with the patient in sitting position after ten
minutes of resting; The average of two readings ve minutes
apart was recorded.

Subject enrollment
At the diabetes clinic of Vali-Asr hospital (Tehran, Iran),
between April and December 2010, we screened 373 consecutive patients who were known cases of type 2 diabetes according to the American Diabetes Association criteria [16]. After
initial assessment, 136 patients meeting the inclusion criteria
were recruited. The inclusion criteria were as follows:
(i) urinary albumin excretion (UAE) 30 mg/24 h in at least
two out of three 24-h urine sample collections; (ii) taking a
combination of an ACE inhibitor (enalapril) and an ARB (losartan) with recommended doses for diabetic nephropathy for
at least the past year and (iii) willingness to participate in the
trial. Subjects were excluded if they had non-diabetic kidney
disease, known cardiovascular or liver disease, chronic kidney
disease stages 4 and baseline serum potassium concentrations 5.5 meq/L. No kidney biopsies were performed to
distinguish diabetic nephropathy from other causes of chronic
kidney disease. Before enrollment, all subjects gave written informed consent. All interventions involving human subjects

Laboratory evaluations
After an overnight 12-h fast, 10 mL of venous blood sample
was collected from each participant. At baseline and follow-up
visits, the patients were also instructed to collect 24-h urine
samples.
Fasting plasma glucose concentrations were measured
using the Glucose Oxidase Method. Fasting insulin concentrations were determined using radioimmunoassay techniques
(Immunotech, Prague, Czech Republic). High-performance
liquid chromatography (HPLC) was performed to assess glycated hemoglobin A1c (HbA1c). Total cholesterol was
2

A. Esteghamati et al.

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ORIGINAL ARTICLE

(RAS) with angiotensin-converting enzyme (ACE) inhibitors


and angiotensin II receptor blockers (ARBs) is indicated in
patients with diabetes who present with micro- or macroalbuminuria [5]. The efcacy of RAS blockade in slowing progression of proteinuria in diabetic and non-diabetic
populations is well recognized [68]. Nevertheless, treatment
with ACE inhibitors and/or ARBs has limitations. A considerable number of patients still progress to renal failure despite
being treated with maximum recommended doses of ACE
inhibitors and/or ARBs. Intriguingly, the ONTARGET trial
demonstrated that combination therapy with ramipril and telmisartan is associated with higher rates of serum creatinine
doubling and dialysis compared with either medication used
alone [9]. These impediments have provided an impetus to
develop more efcacious treatment strategies. It is suggested
that blockade of aldosterone as the end product of RAS provides additional benets in terms of prevention of kidney
damage by means of reducing inammation, oxidative stress
and brosis [10]. It seems likely that mineralocorticoid receptor blockade using aldosterone antagonists, when used in combination with ACE inhibitors and/or ARBs, lowers the risk of
renal disease progression independent of blood pressure (BP)lowering effects [11, 12]. However, randomized clinical trials
in this regard have mainly evaluated the benecial effects of
addition of aldosterone blockers to ACE inhibitors, or a combination of ACE inhibitors and ARBs (i.e. triple blockade of
RAS) [1315]. To date, evidence assessing whether addition of
aldosterone blockade to an ARB-based regimen offers benets
similar to those of addition to an ACE inhibitor-based or combined ACE inhibitor/ARB-based regimen is lacking. Therefore,
the present randomized clinical trial was designed to evaluate
the efcacy of spironolactone (SPR) plus losartan with respect
to BP control, proteinuria reduction and renal function preservation in a sample of patients with type 2 diabetes and diabetic
nephropathy.

measured using enzymatic methods (Pars Azmun, Karaj, Iran).


Sodium and potassium concentrations were determined using
the ame photometry method. The Jaffe method was employed
to assess serum creatinine (Pars Azmun, Karaj, Iran). Estimated
glomerular ltration rate (eGFR) was calculated using the
formula of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) [17]. No calibration of creatinine levels to
standardized reference values was done before eGFR calculation. UAE was measured by colorimetric methods using commercial kits (ZiestChem Diagnostics, Tehran, Iran).

in the SPR/ARB group and 62% of ACE/ARB subjects were


previously diagnosed with hypertension. In addition to enalapril and losartan, 25 patients in the SPR/ARB group and
21 patients in the ACE/ARB group were also taking beta
blockers (atenolol or metoprolol). Moreover, six SPR/ARB
and seven ACE/ARB patients also took diltiazem or amlodipine for BP control. Baseline UAE ranged from 31.0 to
2900.00 mg/24 h. Baseline eGFR ranged from 31.26 to 109.66
mL/min/1.73 m2. Baseline values of all target variables including SBP, DBP, UAE, serum creatinine and eGFR were similar
between the two groups (Table 1).
Mean changes in target variables in the SPR/ARB and
ACE/ARB groups are presented in Table 2.

Within-group changes in ACE inhibitor/ARB


Continuation of ACE/ARB over the course of 18 months
did not signicantly change SBP, DBP, UAE or serum creatinine (Table 2). On the other hand, patients experienced a signicant decline in eGFR by the end of trial (P = 0.013).
Comparative efcacy of interventions
Comparative efcacy of two treatment strategies in
reduction of target variables is delineated in Table 3. SBP decreased more signicantly in SPR/ARB group compared with
ACE inhibitor/ARB after 3, 12 and 18 months (P = 0.009,
0.001 and <0.001, respectively). A gradual increasing trend in
effect size was noted; while addition of SPR generated a small
effect in SBP reduction, it grew to medium and large effect
sizes at 12 and 18 months, respectively (Table 3). SPR/ARB
was superior to ACE inhibitor/ARB in reduction of DBP after
12 and 18 months, but not after 3 months (P = 0.129, 0.046
and 0.001, respectively).
While UAE reduction was comparable between the two
groups after 3 months, SPR/ARB performed signicantly
better after 12 and 18 months (P = 0.031 and 0.017, respectively). It is conceivable that UAE reduction in the SPR/ARB
group is confounded by the concomitant reduction in SBP and
DBP. However, after adjustment for mean SBP and DBP over
the trial period, SPR/ARB was still signicantly more effective
(P = 0.042, effect size: 4.33% for 12 months and P = 0.038,
effect size: 7.0% for 18 months), suggesting that the UAE
reduction by SPR cannot be solely attributed to concomitant
reduction in BP. Moreover, as evident in Figure 2, UAE in

R E S U LT S
One hundred and thirty-six patients met the inclusion criteria
and were allocated to either the SPR/ARB or the ACE inhibitor/ARB arm of the trial (Figure 1). All patients completed a
3-month follow-up. A total of 114 patients returned for the
12-month visit (16.2% were excluded or lost to follow-up).
Finally, 18 months after trial initiation, the 97 remaining
patients were evaluated.
A comparison of clinical and demographic variables of
patients who completed the trial and those lost to follow-up at
either the 12th or the 18th month can be found in Supplementary data, Table S1.
Baseline clinical and demographic data for each arm of the
trial are provided in Table 1. Fifty-ve percent of the patients
3

Spironolactone and proteinuria

ORIGINAL ARTICLE

Within-group changes in SPR/ARB


SBP and DBP signicantly decreased after 18 months
(P = 0.014 and 0.019, respectively). This was accompanied by a
signicant decline in UAE (P < 0.001). Additionally, eGFR signicantly declined over the study period (P = 0.003). During
the trial period, an average increase of 0.2 meq/L in potassium
concentrations was noted (K = 4.44 0.45 meq/L at baseline
and 4.65 0.54 meq/L at the 18th month). In three patients,
SPR was discontinued because of asymptomatic hyperkalemia.
After SPR discontinuation, all the three patients were followed
up and potassium levels returned to normal values within 6
months. Of note, all of the patients experienced a signicant
rise in UAE values after SPR discontinuation (438.0, 36.0,
177.0 versus 1517.5, 259.0, 1127.5 mg/24 h).

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Statistical analysis
Continuous variables with normal distribution are expressed
as mean standard deviation (SD) and categorical variables as
proportions or ratios. Distribution of UAE values did not
comply with the assumption of normality and logarithmic
transformation was necessary to correct right-sided skewness.
In all analyses log-transformed values were used instead. UAE
values are presented as median (interquartile range). The baseline characteristics of the study participants were compared
using independent t-test or chi square, where appropriate. The
baseline characteristics of patients who completed the study and
those who were lost to follow-up were also compared to evaluate
whether loss to follow-up occurred at random. Within-group
changes of outcome variables after 12 and 18 months were assessed using paired t-test. Comparative efcacy of interventions
in short term (3 months), medium term (12 months) and long
term (18 months) was determined using mixed betweenwithin
analysis of variance (ANOVA) method. In each analysis, effect
size was calculated from partial eta squared (based on Cohens
recommendations: 1% small effect, 6% medium effect, 13.8%
large effect). Visit-to-visit changes in outcome variables were
examined by post hoc analysis using the Tukeys least signicant
difference (LSD) method. Additionally, mixed betweenwithin
ANOVA models, with mean SBP and DBP introduced as covariate, were constructed to assess whether the observed differences between two interventions with respect to parameters of
kidney function are confounded by changes in BP over the trial
period. All statistical analyses were performed using SPSS
version 19.0 (IBM Corporation, New York, United States).
A P-value of <0.05 was considered statistically signicant.

ORIGINAL ARTICLE

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F I G U R E 1 : Recruitment, randomization and follow-up of patients. Between April and December 2010, 373 type 2 diabetes patients were

screened. One hundred and thirty-six patients were eligible and were randomly allocated to trial arms. Patients were followed up regularly every
3 months for up to 18 months and the trial was completed in May 2012. Intervention in three patients in the SPR/ARB group was discontinued
due to laboratory abnormalities in serum potassium. Another patient was asked to stop taking SPR due to bothersome gynecomastia. Main
reasons for discontinued intervention as stated by patients included (i) personal issues; (ii) nancial restraints keeping them from frequent travel
to Tehran in those not residing in the capital and (iii) Preferring receiving care from the private sector rather than a teaching hospital.
Abbreviations: SPR, spironolactone; ARB, angiotensin II receptor blocker; ACE inhibitor, angiotensin-converting enzyme inhibitor.

SPR/ARB group reached a nadir at around the 9th month, and


it was relatively sustained thereafter. Post hoc analysis replicated the same; while UAE change from baseline to the 9th
month was statistically signicant (P = 0.006), it did not
change considerably from the 9th to the 18th months
(P = 0.381).
Neither intervention proved to be superior in preventing
creatinine increase or eGFR decline after three, 12 or
18 months (Table 3). Similar ndings were replicated after

controlling for the effect of mean SBP and DBP (data not
shown). Post hoc analysis of eGFR revealed a signicant
decline of 3.5 mL/min/1.73 m2 3 months after trial initiation
(P = 0.015 for baseline to third month). After that, patients
in the SPR/ARB group experienced an indolent but progressive decline in eGFR. Similar analyses for ACE inhibitor/ARB
group revealed no signicant difference in visit-to-visit
decline of eGFR (P > 0.05 for all tests). Overall, the monthly
decline rate of eGFR was 0.441 and 0.410 mL/min/1.73 m2 in
4

A. Esteghamati et al.

Table 1. Baseline characteristics of the trial participants


SPR/ARB

ACE inhibitor/ARB

P-value

74

62

Age (years)

57.80 8.91

58.33 9.33

0.729

Sex (female/male)

23/51

22/40

0.587

Anti-diabetes medication

0.419

Metformin

34 (46%)

28 (45%)

Glibenclamide

4 (6%)

6 (10%)

Metformin + glibenclamide

35 (47%)

26 (42%)

Insulin

1 (1%)

2 (3%)

Duration of diabetes (years)

11.59 7.80

12.41 8.49

0.548

Hypertension (%)

45 (55%)

39 (62%)

0.497

Anti-hypertension medication

0.363
25 (30%)

21 (33%)

Calcium channel blockers

6 (7%)

7 (11%)

Anti-hyperlipidemia medication

0.749
33 (44.6%)

33 (53.2%)

Fibrates

8 (10.8%)

7 (11.3%)

Statins + brates

6 (8.1%)

4 (6.5%)

FPG (mmol/L)

9.86 3.71

9.75 3.43

0.852

Fasting insulin (pmol/L)

73.96 54.80

89.73 42.64

0.442

HbA1c (mmol/mol)

64.63 12.33

63.19 11.71

0.604

Sodium (mmol/L)

139.95 2.46

139.87 2.61

0.855

Potassium (mmol/L)

4.40 0.43

4.32 0.44

0.304

Total cholesterol (mmol/L)

4.54 0.086

4.44 1.16

0.554

Triglycerides (mmol/L)

1.97 1.03

1.92 1.03

0.776

SBP (mmHg)

134.27 18.12

140.08 18.67

0.061

DBP (mmHg)

82.26 8.54

83.17 10.29

0.558

UAE (mg/24 h)

112.0 (63.5, 317.3)

95.0 (50.0, 330.0)

0.727

Target variables

Albuminria

0.796

Microalbuminuria

54 (73.0%)

44 (71.0%)

Marcoalbuminria

20 (27.0%)

18 (29.0%)

92.82 23.87

99.01 24.75

0.152

73.75 16.78

69.13 19.69

0.131

Serum creatinine (mol/L)


2

eGFR (mL/min/1.73 m )

Abbreviations: SPR/ARB, spironolactone + angiotensin II receptor blocker; ACE inhibitor/ARB, angiotensin converting enzyme
inhibitor + angiotensin II receptor blocker; FPG, fasting plasma glucose; HbA1c, glycosylated hemoglobin A1c; SBP, systolic blood pressure;
DBP, diastolic blood pressure; UAE, urinary albumin excretion; eGFR, estimated glomerular ltration rate.
a
Microalbuminuria was dened as 30 mg/24 h UAE < 300 mg/24 h, and macroalbuminuria as UAE 300 mg/24 h.

SPR/ARB and ACE inhibitor/ARB, respectively. To assess


whether the decline rate between groups would be different if
the early drop in SPR/ARB group is ignored, the analysis was

repeated with treating the third-month values as baseline.


Again, between-group comparison indicated no signicant
difference (F = 0.099, P = 0.755).
5
Spironolactone and proteinuria

ORIGINAL ARTICLE

Statins

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Beta blockers

Table 2. Mean changes in target variables in the trial arms


Baseline

12 months

Difference (95% CI)a

P-value

SBP (mmHg)

133.57 17.20

126.71 12.59

6.86 (10.65, 3.06)

0.001

DBP (mmHg)

82.64 8.54

79.14 5.31

3.50 (5.62, 1.38)

0.002

UAE (mg/24 h)

106.0 (55.5, 306.3)

39.5 (19.0, 127.5)

52.5 (208.8, 13.8)

<0.001

91.94 22.10

103.43 43.32

+11.49 (+2.65, +21.22)

0.013

73.98 15.79

66.88 18.77

7.11 (11.13, 3.08)

0.001

Baseline

18 months

Difference (95% CI)

SBP (mmHg)

134.17 16.45

125.28 17.15

8.89 (15.88, 1.89)

0.014

DBP (mmHg)

83.05 9.80

78.61 7.98

4.44 (8.10, 0.79)

0.019

UAE (mg/24 h)

105.0 (62.5, 281.8)

29.0 (16.5, 69.4)

60.5 (148.8, 16.4)

<0.001

92.82 15.91

141.44 222.77

+48.62 (27.40, 124.64)

0.202

74.39 15.47

64.16 20.73

10.23 (16.69, 3.76)

0.003

Baseline

12 months

Difference (95% CI)

SBP (mmHg)

141.27 18.73

137.45 21.43

3.82 (10.15, +2.50)

0.230

DBP (mmHg)

83.40 10.42

81.20 7.73

2.20 (5.66, +1.26)

0.207

UAE (mg/24 h)

74.0 (45.0330.0)

63.0 (23.0205.0)

20.0 (81.0, +27.0)

0.120

Serum creatinine (mol/L)

98.12 23.87

106.08 38.90

+7.96 (1.77, 18.56)

0.110

eGFR (mL/min/1.73 m2)

68.36 19.45

63.19 20.50

5.17 (10.49, +0.15)

0.056

Baseline

18 months

Difference (95% CI)

SBP (mmHg)

144.11 21.65

138.03 22.70

6.08 (14.71, +2.57)

0.161

DBP (mmHg)

86.07 11.00

83.21 6.12

2.86 (7.06, +1.34)

0.207

UAE (mg/24 h)

82.5 (44.3, 340.5)

105.5 (25.3, 510.8)

+22.0 (110.3, 108.9)

0.809

94.59 20.33

106.08 38.90

+11.49 (0.88, 23.87)

0.059

69.35 19.49

60.27 20.47

9.08 (16.06, 2.10)

0.013

SPR/ARB

Serum creatinine (mol/L)


2

eGFR (mL/min/1.73 m )

Serum creatinine (mol/L)


eGFR (mL/min/1.73 m )

P-value

ORIGINAL ARTICLE

ACE inhibitor/ARB

Serum creatinine (mol/L)


2

eGFR (mL/min/1.73 m )

P-value

Abbreviations: SPR/ARB, spironolactone + angiotensin II receptor blocker; ACE inhibitor/ARB, angiotensin-converting enzyme
inhibitor + angiotensin II receptor blocker; SBP, systolic blood pressure; DBP, diastolic blood pressure; UAE, urinary albumin excretion;
eGFR, estimated glomerular ltration rate.
a
A positive sign indicates increase, whereas negative signs denote decrease in outcome variables.

to baseline kidney function, pre-existing hypertension and


previous anti-hypertensive treatments are likely to underline
this discrepancy. In our sample, more than half of the participants were already diagnosed with hypertension, and more
than two-thirds had baseline BP values higher than 130/80. In
a systematic review of SPR trials (2008), it was shown that ve
out of six trials that reported a signicant drop in BP enrolled
subjects with initial values of greater than 130/80 mmHg [20].
Herein, SPR/ARB reduced UAE independent of SBP and
DBP. In a randomized trial of 165 patients with chronic glomerulonephritis of idiopathic origin already treated with ACE
inhibitor and/or ARB, addition of SPR 25 mg daily signicantly abated albuminuria by 58% after 12 months [13]. In

DISCUSSION
In the present study, replacement of enalapril with SPR proved
to be signicantly more effective than continuation of dual
RAS blockade in reduction of both SBP and DBP over a
follow-up period of 18 months (9 mmHg in SBP and 5 mmHg
in DBP). Rossing and colleagues (2005) found a signicant
reduction of about 10 mmHg in SBP and 5 mmHg in DBP
after addition of SPR 25 mg daily in 21 type 2 diabetes patients
[15]. Contrary to these observations, some have reported that
SPR at the doses used for proteinuria reduction does not affect
BP [18, 19]. Differences in the patients recruited with respect
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P-value

Table 3. Comparison of medication efcacy on improvement of blood pressure, microalbuminuria and renal function
Baseline

3 months

P-value

Effect size

SPR/ARB

ACE inhibitor/ARB

SPR/ARB

ACE inhibitor/ARB

SBP (mmHg)

134.27 18.12

140.08 18.67

130.00 14.74

137.38 17.74

7.04

0.009

4.7%

DBP (mmHg)

82.26 8.54

83.17 10.29

80.37 7.10

83.25 9.72

2.33

0.129

1.6%

UAE (mg/24 h)

112.0 (63.5, 317.3)

95.0 (50.0, 330.0)

69.5 (28.8, 168.5)

105.0 (48.6, 234.0)

1.53

0.218

1.1%

92.82 23.87

99.01 24.75

98.12 22.98

97.24 22.10

0.34

0.559

0.2%

73.75 16.78

69.13 19.69

70.82 17.91

70.78 19.43

0.77

0.382

0.5%

12.70

0.001

9.6%

Serum creatinine (mol/L)


2

eGFR (mL/min/1.73 m )

Baseline

12 months

SPR/ARB

ACE/ARB

SPR/ARB

ACE/ARB

SBP (mmHg)

133.57 17.20

141.27 18.73

126.71 12.59

137.45 21.43

DBP (mmHg)

82.64 8.54

83.40 10.42

79.14 5.31

81.20 7.73

4.07

0.046

3.3%

UAE (mg/24 h)

106.0 (55.5, 306.3)

74.0 (45.0330.0)

39.5 (19.0, 127.5)

63.0 (23.0205.0)

4.13

0.044

3.4%

91.94 22.10

98.12 23.87

105.20 41.55

105.20 28.29

0.02

0.900

<0.1%

73.72 15.59

68.71 19.35

66.96 17.57

65.48 19.94

0.20

0.652

0.2%

Serum creatinine (mol/L)


2

eGFR (mL/min/1.73 m )

Baseline

18 months
ACE/ARB

SPR/ARB

ACE/ARB

SBP (mmHg)

134.17 16.45

144.11 21.65

125.28 17.15

138.04 22.70

13.88

<0.001

18.3%

DBP (mmHg)

83.06 9.80

86.07 11.00

78.61 7.98

83.21 6.12

12.14

0.001

16.4%

UAE (mg/24 h)

105.0 (62.5, 281.8)

82.5 (44.3, 340.5)

29.0 (16.5, 69.4)

105.5 (25.3, 510.8)

5.70

0.020

8.4%

92.82 15.91

94.59 20.22

105.20 24.75

110.50 32.71

0.06

0.802

0.1%

73.97 15.83

69.17 19.29

66.03 17.29

61.79 20.58

0.18

0.674

0.3%

Serum creatinine (mol/L)


2

eGFR (mL/min/1.73 m )

Abbreviations: SPR/ARB, spironolactone + angiotensin II receptor blocker; ACE inhibitor/ARB, angiotensin-converting enzyme inhibitor + angiotensin II receptor blocker; UAE, urinary
albumin excretion; SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular ltration rate.

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Spironolactone and proteinuria

SPR/ARB

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F I G U R E 2 : Mean changes in outcome variables over the trial course (18 months, seven visits). Variables are presented as mean standard

error. For UAE, log-transformed values are presented. P-values for between-group comparisons: systolic blood pressure (P < 0.001); diastolic
blood pressure (P = 0.001); urinary albumin excretion (P = 0.017); serum creatinine (P = 0.802); estimated glomerular ltration rate (P = 0.674).
Abbreviations: SPR, spironolactone; ARB, angiotensin II receptor blocker; ACE inhibitor, angiotensin-converting enzyme inhibitor.

8
A. Esteghamati et al.

Supplementary data are available online at http://ndt.oxfordjournals.org.

C O N F L I C T O F I N T E R E S T S TAT E M E N T
None declared.
9
Spironolactone and proteinuria

ORIGINAL ARTICLE

S U P P L E M E N TA R Y D ATA

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quite commonly with reports indicating prevalence rates as


high as 22% with ARBs [32] and 40% with ACE inhibitors [33].
Treatment of aldosterone escape with SPR has been effective in
reduction of proteinuria [32]. Hence, it is plausible that
additional blockade of aldosteronevia mineralocorticoid receptor antagonistsmay result in more efcacious blockade of
the RAAS system. It is suggested that low doses of SPR exert
antiproteinuric effects mainly via the non-genomic pathway;
our ndings, along with a number of previous reports,
indicate that these effects are indeed independent of BP control
[14, 3436]. Non-genomic effects of aldosterone may involve
inammation, oxidative stress, endothelial dysfunction and subsequent apoptosis and brosis in podocytes [10, 3739].
A number of limitations in our study should be considered.
First, during the course of the trial, a relatively high rate of loss
to follow-up was observed. Nevertheless, comparison of the
baseline characteristics of patients who completed the study
and who were lost to follow-up at the 12th and the 18th
months revealed no signicant differences between the two
groups. This nding supports the notion that dropout of
patients has occurred at random. Second, the present study
was an open-label trial and no placebo-control was carried
out. This might have contributed to potential bias in the assessment of patients. Despite these limitations, our study is
unique in the sense that for the rst time, it examines the
effects of combined SPR/losartan regimen on diabetic nephropathy, and extends the duration of follow-up beyond that in
previous reports. Based on our ndings, addition of SPR to an
ARB-based regimen provides additional benets with respect
to BP control and proteinuria diminution. However, benecial
effects of SPR on UAE reduction should be interpreted with
caution, since aldosterone blockade does not slow the progression of eGFR loss during the 18 months of trial. Nevertheless, it should be noted that there is ample evidence indicating
that reduction of microalbuminuria per se offers renoprotection in diabetic nephropathy [28, 40]. On the other hand, sustained BP-lowering effects of SPR also contributes to
preservation of renal function in patients with diabetes and
hypertension [4144]. What remains to be elucidated is
whether observed improvements with SPR does in fact prevent
hard outcomes including cardiovascular events, creatinine
doubling, progression to ESRD and need for temporary or permanent dialysis. Future large multicenter RCTs with eventbased outcomes and longer durations of follow-up are paramount to evaluate long-term effects of reduced proteinuria by
SPR on eGFR preservation.

another trial of 81 type 2 diabetes patients, addition of SPR


25 mg daily was more effective than addition of losartan
(100 mg daily) to a maximally dosed ACE inhibitor regimen
[21]. Similar results have been replicated using either SPR or
eplerenone in diabetic populations [2224].
In patients taking SPR/ARB, the steepest decline in UAE
was observed in the rst 3 months. Congruently, in an 8-week
trial of SPR in 42 patients with chronic kidney disease, 75% of
antiproteinuric effects of SPR were apparent 2 weeks after trial
initiation [25]. It seems that there is an early kick-start in SPR
effects on glomerular ltration of proteins; the proteinuria is
then sustained. It is unclear, however, for how long this benecial effect is prolonged since the majority of studies in this
regard have followed patients for no longer than 12 months.
To our knowledge, our study is among the rst to extend the
follow-up duration of patients to up to 18 months. Our results
point to a possible long-term benet for SPR in UAE diminution, since albuminuria was maintained and did not return to
baseline values by the end of trial.
Here, a progressive decline in eGFR concentrations was observed in both groups, and the between-group difference did
not reach statistical signicance (about 9 mL/min/1.73 m2 in
SPR/ARB group and 8 mL/min/1.73 m2 in ACE inhibitor/
ARB group). Moreover, it persisted even after adjustment for
SBP and DBP. SPR initiation resulted in a sudden and signicant decline in eGFR of about 4 mL/min/1.73 m2 after 3
months. A similar observation has been made by other research groups [15, 26]. Bianchi and colleagues reported a signicant drop of about 5 mL/min/1.73 m2 as early as 4 weeks
after SPR was added, followed by a stable rate of monthly
decline (0.323 versus 0.474 in case and control groups, respectively, P < 0.01) [13]. This was not the case in our study,
however. Our analyses conrmed that even if the early eGFR
changes in the SPR/ARB group is disregarded, SPR does not
offer additional renoprotection with respect to eGFR decline.
Similar initial drops have been reported with both captopril
and irbesartan [27, 28]. While mechanisms underlying this
early decline remain obscure for the most part, it is likely that
hemodynamic alterations caused by suppression of genomic
effects of aldosterone contribute to this phenomenon [13, 26].
Asymptomatic hyperkalemia occurred in only three patients
in our trial (3.6%) and resolved soon after SPR discontinuation.
Hyperkalemia is a major limiting factor in administration of
aldosterone antagonists and, if left undetected, could lead to signicant mortality and morbidity [29, 30]. However, our results
demonstrated that the addition of SPR to ARB is relatively safe,
mostly due to well-preserved renal function of trial participants
(mean baseline eGFR in patients with hyperkalemia was 74 mL/
min/1.73 m2). In line with previous reports [26, 29], in our
sample, hyperkalemia occurred in patients who were older and
had higher baseline potassium concentrations. Therefore, frequent assessment of serum potassium in patients with elevated
potassium due to prior treatment with ACE inhibitors and/or
ARBs, advanced age and diminished GFR is advisable.
The detrimental effects of aldosterone are not adequately
arrested by the use of ACE inhibitor, ARB or a combination of
both [31], and aldosterone escape might play an important role
in this regard [32]. It is believed that aldosterone escape occurs

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Received for publication: 22.11.2012; Accepted in revised form: 11.5.2013

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Spironolactone and proteinuria

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