AJN Patient-Oriented, Translational Research: Research Article

American Journal
of Nephrology Am J Nephrol Received: July 2, 2023
Accepted: September 26, 2023
DOI: 10.1159/000534366 Published online: October 4, 2023

Effects of Mineralocorticoid Receptor

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Antagonists for Chronic Kidney Disease:
A Systemic Review and Meta-Analysis
Chen-Yi Yuan a, b Yuan-Cheng Gao c Yi Lin d Lin Liu a Xiao-Gang Shen a
Wen-Li Zou a Min-Min Wang a Quan-Quan Shen a Li-Na Shao a
Yue-Ming Liu a Jia-Wei Zhang a Zhi-Hui Pan d Yan Zhu d Jing-Ting Yu d
Xu-Guang Yu e Bin Zhu a
a
Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated
People’s Hospital, Hangzhou Medical College, Hangzhou, China; bDepartment of Nephrology, The First
Affiliated Hospital of Ningbo University, Ningbo, China; cDepartment of Nephrology, Zhejiang Hospital of Chinese
Medicine, Affiliated to Zhejiang University of Chinese Medicine, Hangzhou, China; dDepartment of Nephrology,
Hangzhou Hospital of Chinese Medicine (Guangxing Hospital), Affiliated to Zhejiang University of Chinese
Medicine, Hangzhou, China; eDepartment of Nephrology, Yueqing People’s Hospital, Wenzhou, China

Keywords CI, −140.17 to −41.64 mg/g), 24-h urinary protein excretion

Mineralocorticoid receptor antagonists · Diabetic kidney
disease · Chronic kidney disease · Meta-analysis
Abstract
Background: Mineralocorticoid receptor blockade could be
a potential approach for the inhibition of chronic kidney
disease (CKD) progression. The benefits and harms of dif-
ferent mineralocorticoid receptor antagonists (MRAs) in CKD
are inconsistent. Objectives: The aim of the study was to
summarize the benefits and harms of MRAs for CKD patients.
Methods: We searched MEDLINE, EMBASE, and the Co-
chrane databases for trials assessing the effects of MRAs on
non-dialysis-dependent CKD populations. Treatment and
adverse effects were summarized using meta-analysis.
Results: Fifty-three trials with 6 different MRAs involving
22,792 participants were included. Compared with the
control group, MRAs reduced urinary albumin-to-creatinine
ratio (weighted mean difference [WMD], −90.90 mg/g, 95%
(WMD, −0.20 g, 95% CI, −0.28 to −0.12 g), estimated glomerular
filtration rate (eGFR) (WMD, −1.99 mL/min/1.73 m2, 95% CI, −3.28
to −0.70 mL/min/1.73 m2), chronic renal failure events (RR, 0.86,
95% CI, 0.79–0.93), and cardiovascular events (RR, 0.84, 95% CI,
0.77–0.92). MRAs increased the incidence of hyperkalemia (RR,
2.04, 95% CI, 1.73–2.40) and hypotension (RR, 1.80, 95% CI,
1.41–2.31). MRAs reduced the incidence of peripheral edema (RR,
0.65, 95% CI, 0.56–0.75) but not the risk of acute kidney injury (RR,
0.94, 95% CI, 0.79–1.13). Nonsteroidal MRAs (RR, 0.66, 95% CI,
0.57–0.75) but not steroidal MRAs (RR, 0.20, 95% CI, 0.02–1.68)
significantly reduced the risk of peripheral edema. Steroidal
MRAs (RR, 5.68, 95% CI, 1.26–25.67) but not nonsteroidal MRAs
(RR, 0.52, 95% CI, 0.22–1.22) increased the risk of breast disorders.
Conclusions: In the CKD patients, MRAs, particularly in combi-
nation with angiotensin-converting enzyme inhibitor/angiotensin
receptor blocker, reduced albuminuria/proteinuria, eGFR, and the
Chen-Yi Yuan and Yuan-Cheng Gao contributed equally to this work.

karger@karger.com © 2023 S. Karger AG, Basel Correspondence to:

www.karger.com/ajn Bin Zhu, zhubing @ hotmail.com
incidence of chronic renal failure, cardiovascular and peripheral
edema events, whereas increasing the incidence of hyperkalemia
and hypotension, without the augment of acute kidney injury
events. Nonsteroidal MRAs were superior in the reduction of
more albuminuria with fewer peripheral edema events and
without the augment of breast disorder events.
© 2023 S. Karger AG, Basel
Introduction
Chronic kidney disease (CKD) is a global health concern
whose medical burden is substantial and increasing. It was
estimated that CKD had a prevalence of 14% in America from
2017 to 2020 [1]. CKD was indicated to be a predominant
cause of mortality worldwide [2]. Diabetes mellitus (DM) has
become the leading cause of CKD [3]. It is estimated that
diabetic kidney disease (DKD) accounts for 30–50% of all
global CKD cases and may increase to 69% by 2030 [4].
Renin-angiotensin-aldosterone system inhibitors are the
major treatment for CKD [5, 6]. However, 40% of CKD
patients receiving angiotensin-converting enzyme inhibitors
(ACEI) or angiotensin receptor blockers (ARB) develop “al-
dosterone breakthrough,” which is associated with insulin
resistance and endothelial dysfunction to aggravate CKD
progression [6, 7]. Aldosterone activates the mineralocorticoid
receptor (MR) in the nonepithelial tissues of the heart and
kidney to induce inflammation and fibrosis, leading to left
ventricular hypertrophy and CKD progression [8, 9]. An-
giotensin blockade is inefficient against the nonclassical
profibrotic actions of aldosterone [10]. CKD patients remain
at a high risk of cardiovascular events (CVEs) and kidney
disease progression despite receiving ACEI/ARB [11, 12].
Then, MR blockade could be a potential approach for the
inhibition of CKD progression [13, 14]. Steroidal MR an-
tagonists (MRAs) have been demonstrated to benefit the heart
and kidney [15]. The new-generation nonsteroidal MRAs
(finerenone, ocedurenone, esaxerenone, and apararenone)
exhibit better selectivity for MR over the other steroidal re-
ceptors [16–18] and appear to have a better benefit-risk ratio
[19–22]. However, the effects of different MRAs on CKD are
inconsistent. This meta-analysis was performed to clarify the
benefits and harms of MRAs for CKD patients.
Materials and Methods
Data Sources, Search Strategy, and Selection Criteria
We performed this systematic review following the PRISMA
guidelines for meta-analyses [23] and registered in PROSPERO
(CRD42023393389). Relevant trials were identified by searching
MEDLINE (from 1950 through November 2022), EMBASE (from
2 Am J Nephrol
DOI: 10.1159/000534366
1966 through November 2022), and the Cochrane Library (Co-
chrane Central Register of Controlled Trials; no date restriction).
Searches were conducted using relevant text words and medical
subject headings, including all spellings of MRA, aldosterone
antagonist, spironolactone, eplerenone, finerenone, esaxerenone,
apararenone, ocedurenone, and CKD for randomized controlled
trials (RCTs) without language restriction. The ClinicalTrials.gov
website and reference lists from identified trials and review articles
were scanned to identify other relevant trials (shown in online
suppl. Table 1; for all online suppl. material, see https://doi.org/10.
1159/000534366).
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Study Selection
The literature search, data extraction, and quality assessment
were independently performed by two investigators (C.-Y.Y. and
Y.-C.G.). All RCTs assessing the effects of MRAs in CKD (defined
as the urinary albumin-to-creatinine ratio [UACR] ≥30 mg/g and
the estimated glomerular filtration rate [eGFR] ≤90 mL/min/
1.73 m2) not receiving renal replacement therapy were eligible for
inclusion. We excluded non-RCT trials, trials with participants
receiving maintenance dialysis or kidney transplantation, or the
trials without a control arm.
Outcome Evaluation
The outcomes assessed included UACR, 24-h urinary protein
(UPE), eGFR, chronic kidney failure events, systolic blood pressure
(SBP), diastolic blood pressure (DBP), serum potassium, CVE, and
all-cause mortality, as well as adverse effects of hyperkalemia,
reproductive system disorders, and breast disorders. Chronic
kidney failure was defined as end-stage kidney disease (defined as
the initiation of long-term dialysis or kidney transplantation, or an
eGFR below 15 mL/min/1.73 m2), or a sustained decrease from
baseline of at least 40% in eGFR. CVEs were defined as a composite
of cardiovascular death, myocardial infarction, myocardial is-
chemia, heart failure, ischemic stroke, and cerebrovascular acci-
dent. Reproductive system disorders were defined as a composite
of gynecological oncology and menstrual disorders. Breast dis-
orders included breast tenderness, breast hyperplasia, and gy-
necomastia. Hyperkalemia, hypotension, and eGFR slope were
defined according to the original trials (shown in online suppl.
Table 2). When these definitions were not provided, alternative,
comparable definitions provided by the trial authors were
included.
Data Extraction and Assessment of Study Quality and Risk
of Bias
Published reports were obtained for each eligible trial, and
relevant data were extracted for analyses. In the multi-dose trial,
we combined subgroups of different MRA doses into a group using
Review Manager 5.4 (Cochrane Collaboration, Oxford, UK) [24].
We contacted the authors when the required data were not
provided in the published articles.
The Cochrane quality criteria were used to assess study quality
and the risk of bias based on random sequence generation, al-
location concealment, blinding, reporting bias, attrition bias, and
any other potential sources of bias. The trials were categorized as
low, medium, or high risk of bias. A graphical view of bias status
was generated with Review Manager 5.4. A third investigator (B.Z.)
adjudicated any disagreements.
Yuan/Gao/Lin/Liu/Shen/Zou/Wang/Shen/
Shao/Liu/Zhang/Pan/Zhu/Yu/Yu/Zhu
 Data Synthesis and Analyses
In calculating risk ratios, the total number of patients in each
group was utilized as the denominator. Individual trial weighted
mean difference (WMD), relative risk (RR), and 95% confidence
interval (CI) were calculated before data pooling.
A random-effects model was adopted as proposed by DerSi-
monian and Laird [25]; the percentage of variability across trials
attributable to heterogeneity beyond chance was estimated using I2
statistics. Publication bias for the efficacy outcomes was assessed
using the funnel plot and Egger’s test. Sensitivity analyses were
conducted to assess the robustness of the results. Subgroup an-
alyses were performed to explore possible sources of heterogeneity.
Univariate meta-regression analysis was performed using the
residual maximum likelihood estimation. Study quality was an-
alyzed based on the Cochrane quality criteria. A two-sided p < 0.05
was considered statistically significant. All statistical analyses were
performed with STATA, version 11 (StataCorp LP).
Results
Literature Search
The literature search yielded 1,447 articles, and 53
trials with 22,792 patients were finally included (shown in
Fig. 1).
Trial Characteristics
The characteristics of the included trials [19, 21,
26–76] were summarized in Table 1. Of them, 39 trials
were RCTs [19, 21, 28–30, 32, 33, 35, 38, 39, 42–44, 46, 47,
50–53, 55–62, 64–75], and 14 were randomized crossover
trials [27, 31, 34, 36, 37, 40, 41, 45, 48, 49, 54, 63, 76, 77],
followed up from 2 to 42 months. The baseline charac-
teristics of the intervention and control groups were
similar within all trials. Thirty trials enrolled 16,102
participants with DKD; nine trials recruited 869 partic-
ipants with non-diabetes CKD; and the other fourteen
trials recruited 5,821 participants with unspecified CKD.
The mean age reported for participants ranged from 34 to
74 years, and the proportion of males ranged from 19% to
100%. Trials sample size varied from 12 to 7,352, and the
publication time ranged from 2005 to 2022. These trials
involved 6 MRA agents including 4 nonsteroidal MRAs of
finerenone (5 trials) [19, 21, 55, 60, 65], esaxerenone (2
trials) [26, 27], apararenone (1 trial) [28], ocedurenone (1
trial) [29], and 2 steroidal MRAs of eplerenone (12 trials)
[30, 34, 40, 45, 49–51, 58, 68, 70, 72, 76], and spi-
ronolactone (33 trials) [26–29, 31–33, 35–39, 41–44,
46–48, 52–57, 59, 61–64, 66, 67, 73]. Ten trials were
placebo-controlled only [31, 44, 50, 55, 67, 68, 72–74, 77].
MRAs were compared with placebo, with background of
ACEi/ARB in thirty-four trials [19, 21, 27–30, 33, 36–39,
41, 42, 45–49, 51, 52, 54, 56–61, 64–66, 69–71, 75]. MRAs
Mineralocorticoid Receptor Antagonists for
Chronic Kidney Disease
were compared with ACEi/ARB in 3 trials [30–32] and
dapagliflozin in one trial [33]. The comparators of di-
uretics (6 trials) comprised hydrochlorothiazide (3 trials)
[34–36], trichlormethiazide and furosemide (3 trials) [37,
38, 39].
Risk of Bias
Of the included trials, one trial [52] was evaluated as
having a low risk of bias, twenty-four trials [19, 21, 29, 31,
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34, 41, 42, 47, 49, 51, 54, 58–62, 64, 65, 68, 69, 71, 73, 75,
76] were identified as having a medium risk of bias, and
twenty-eight trials [26–28, 30, 32, 33, 35–40, 43–46, 48,
50, 52, 53, 55–57, 63, 66, 70, 72, 74] as having a high risk
of bias. All trials were reported to be randomized; 14 trials
(26%) had clear allocation concealment methods; 33 trials
(62%) described blinding of participants and personnel.
38 trials (72%) completely reported the outcomes. Se-
lective reporting was judged to be at low risk of bias in 29
trials (55%), and high risk in 16 (30%). Other biases in 23
trials (43%) were judged to be low risk. However, de-
tection bias was unclear in 32 trials (60%) (shown in
online suppl. Fig. 1, 2).
Outcomes
Effects on UACR/UPE
Data regarding the effects of MRAs compared to
placebo on UACR were available from 10 trials with
14,033 participants. Overall, MRAs decreased UACR by
90.90 mg/g (10 trials, 95% CI, −140.17 to −41.64 mg/g)
compared with the control. All MRAs showed consistent
evidence of UACR reduction, while finerenone reduced
UACR more significantly (finerenone: WMD, −256.86 mg/g,
95% CI, −425.02 to −88.17 mg/g; esaxerenone: WMD,
−56.40 mg/g, 95% CI, −103.39 to −9.41 mg/g; eplerenone:
WMD, −26.10 mg/g, 95% CI, −48.98 to −3.22 mg/g; spi-
ronolactone: WMD, −74.08 mg/g, 95% CI, −188.18
to −40.02 mg/g, p for interaction = 0.004) (shown in Fig. 2).
Consistently, MRAs decreased UPE by 0.20 g (8 trials, 95%
CI, −0.28 to −0.12 g) compared with the control group
(shown in online suppl. Fig. 3).
Effects on Kidney Function
The effects of MRAs on eGFR were reported in 36 trials
with 18,936 patients. Overall, compared with the control
group, MRAs significantly decreased eGFR by 1.99 mL/
min/1.73 m2 (36 trials, 95% CI, −3.28 to −0.70 mL/min/
1.73 m2) with significant heterogeneity among various
MRAs (apararenone: 1 trial, WMD, −7.97 mL/min/
1.73 m2, 95% CI, −10.76 to −5.18 mL/min/1.73 m2;
Am J Nephrol 3
DOI: 10.1159/000534366

Fig. 1. Diagram of the identification process for eligible studies. RCT, randomized controlled trial.
finerenone: 3 trials, WMD, −3.80 mL/min/1.73 m2, 95%
CI, −5.67 to −1.92 mL/min/1.73 m2; esaxerenone: 1 trials,
WMD, −6.01 mL/min/1.73 m2, 95% CI, −12.08 to 0.06
mL/min/1.73 m2; eplerenone: 10 trials, WMD, −1.08 mL/
min/1.73 m2, 95% CI, −2.40 to 0.23 mL/min/1.73 m2;
spironolactone: 21 trials, WMD, −0.52 mL/min/1.73 m2,
95% CI, −3.52 to 2.48 mL/min/1.73 m2, p for interac-
tion <0.001) (shown in Fig. 3).
Effects on Outcome of Chronic Kidney Failure
Four trials involving 14,397 patients recorded 1,914
chronic kidney failure events. Overall, MRAs signifi-
cantly reduced the risk of developing chronic kidney
failure (4 trials, RR, 0.86, 95% CI, 0.79–0.93) that was
mainly driven by finerenone (2 trials, RR, 0.86, 95% CI,
0.79–0.93), without significant heterogeneity among
different MRAs (p for interaction = 0.93) (shown in
online suppl. Fig. 4). Separately, MRAs significantly
reduced the risk of outcome of eGFR decline by ≥40%
4 Am J Nephrol
DOI: 10.1159/000534366
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from baseline (3 trials, RR, 0.85, 95% CI, 0.78–0.92).
MRAs did not significantly reduce the risk of devel-
oping ESRD (3 trials, RR, 0.87, 95% CI, 0.74–1.01)
(shown in online suppl. Fig. 5).
Effects on Blood Pressure
MRAs significantly reduced SBP by 3.88 mm Hg (33
trials, 95% CI, −5.11 to −2.65 mm Hg) and DBP by
1.27 mm Hg (31 trials, 95% CI, −1.99 to −0.56 mm Hg),
respectively, without significant heterogeneity among
the different MRAs (p for interaction for SBP = 0.06; p
for interaction for DBP = 0.1) (shown in online suppl.
Fig. 6).
Effects on Serum Potassium
MRAs increased serum potassium by 0.18 mmol/L (32
trials, 95% CI, 0.14–0.22 mmol/L) without significant
heterogeneity among various MRAs (p for interaction =
0.3) (shown in online suppl. Fig. 7).
Yuan/Gao/Lin/Liu/Shen/Zou/Wang/Shen/
Shao/Liu/Zhang/Pan/Zhu/Yu/Yu/Zhu
 Table 1. Characteristics of included trials

Study Disease Patients, Age, Malea Intervention Follow-up UACR, mg/g eGFR, mL/min/1.73 m2 SBP, mm Hg DBP, mm Hg
n years duration,
months
experimental control group background therapy experimental control group experimental control experimental control experimental control
group group group group group group group group

FIGARO-DKD DKD 7,352 64 69 Finerenone, Usual care ACEI/ARB 41 586.40±764.60 586.90±752.70 67.60±21.60 68.00±21.70 135.80±14.00 135.70±14.10 76.70±9.50 76.80±9.50
[21] (2021) 10–20 mg/d
FIDELIO-DKD DKD 5,674 66 70 Finerenone, Usual care ACEI/ARB 31 1,185.90±1,036.90 1,210.30±1,052.30 44.40±12.50 44.30±12.60 138.10±14.30 138.00±14.40 75.80±9.70 75.80±9.70
[19] (2020) 10–20 mg/d
ARTS-DN [40] DKD 48 64 88 Finerenone, Usual care ACEI/ARB 3 194.87±278.32 256.80±166.31 65.13±12.85 60.88±16.53 137.25±16.35 135.72±16.90 77.71±10.11 69.25±11.63

Chronic Kidney Disease

(2017) 10–20 mg/d
ARTS-DN [41] DKD 437 64 76 Finerenone, Usual care ACEI/ARB 3 211.94±179.57 188.40±169.80 66.83±22.31 72.20±20.40 137.77±14.32 139.90±14.30 76.63±9.98 78.20±9.70
(2015) 10–20 mg/d
Pitt et al. [42] CKD 132 73 83 Finerenone, Usual care General therapy 4 23.70±5.20 22.20±5.60 47.00±10.90 46.90±8.20 / / / /
(2013) 10 mg/d
Ito et al. [27] DKD 449 66 77 Esaxerenone, Usual care ACEI/ARB 13 / / 69.00±18.00 69.00±18.00 140.00±10.00 140.00±10.00 82.00±8.00 84.00±8.00
(2020) 1.25–2.5 mg/d
Ito et al. [26] DKD 215 65 78 Esaxerenone, Usual care ACEI/ARB 3 126.00±63.60 123.00±58.00 66.99±18.46 69.00±19.00 138.01±11.58 138.00±11.00 / /
(2019) 1.25–2.5 mg/d
Wada et al. [28] DKD 292 62 76 Apararenone, Placebo ACEI/ARB 24 / / 74.09±20.25 77.50±20.50 / / / /
(2021) 2.5–10 mg/d

Mineralocorticoid Receptor Antagonists for

Bakris et al. [29] CKD 162 65 55 Ocedurenone, Placebo General therapy 3 / / / / 155.02±14.85 155.80±10.84 88.69±12.58 85.90±11.46
(2021) 0.25–0.5 mg/d
Provenzano CKD 46 70 76 Eplerenone, Dapagliflozin, 10 mg/d ACEI/ARB 6 / / 57.20±18.00 56.80±18.00 135.00±14.00 135.00±12.00
et al. [33] (2022) 50 mg/d
Provenzano CKD 46 70 76 Eplerenone, Usual care Dapagliflozin, 10 mg/ 6 / / 58.40±19.00 56.80±18.00 133.00±11.00 135.00±12.00 / /
et al. [33] (2022) 50 mg/d d, ACEI/ARB
El Mokadem DKD 50 49 56 Eplerenone, Usual care ACEI/ARB 6 165.40±62.94 159.96±66.22 72.84±11.93 71.80±8.46 146.36±5.39 145.00±5.00 90.91±3.98 90.65±3.79
et al. [32] (2020) 50 mg/d
El Mokadem DKD 50 50 56 Eplerenone, Ramipril 10, mg/d General therapy 6 154.33±67.15 159.96±66.22 72.28±8.85 71.80±8.46 143.50±5.80 145.00±5.00 90.83±3.81 90.65±3.79
et al. [32] (2020) 50 mg/d
Minakuchi et al. CKD 48 67 / Eplerenone, Usual care General therapy 36 / / 65.20±16.84 63.90±19.02 131.90±10.83 132.10±10.40 76.60±6.85 76.30±5.46
[43] (2020) 25 mg/d
Ferreira et al. CKD 1,152 71 77 Eplerenone, Usual care General therapy 21 / / 63.00±20.00 62.00±20.00 123.00±18.00 122.00±17.00 / /
[44] (2019) 50 mg/d
Ando et al. [45] CKD 342 59 63 Eplerenone, Usual care ACEI/ARB 13 163.10±148.00 156.80±133.60 67.70±14.30 68.60±13.60 138.60±11.10 138.80±12.60 82.40±10.20 81.90±10.00
(2014) 50 mg/d
Boesby et al. [46] CKD 54 55 19 Eplerenone, Usual care General therapy 6 / / 36.00±10.00 35.00±13.00 126.00±10.00 127.00±17.00 73.00±8.00 75.00±10.00
(2013) 25–50 mg/d
EMPHASIS-HF CKD 2737 69 78 Eplerenone, Usual care ACEI/ARB 42 / / 71.20±21.90 70.40±21.70 124.00±17.00 124.00±17.00 / /
[47] (2013) 25–50 mg/d
Tylicki et al. [48] CKD 18 39 78 Eplerenone, Usual care ACEI/ARB 10 / / 94.00±34.37 94.00±34.37 116.80±10.18 116.80±10.18 79.90±7.64 79.90±7.64
(2012) 50 mg/d
Boesby et al. [49] CKD 40 / 68 Eplerenone, Usual care ACEI/ARB 2 / / 82.00±39.09 82.00±39.09 125.00±13.00 125.00±13.00 86.00±10.00 86.00±10.00

Am J Nephrol
(2011) 25 mg/d
Morales et al. CKD 12 57 58 Eplerenone, Lisinopril, 20 mg/d General therapy 11 / / 57.30±29.10 56.20±30.00 139.00±16.50 139.00±16.50 77.67±8.50 77.67±8.50
[31] (2009) 25 mg/d
Joffe et al. [34] DKD 16 / 82 Eplerenone, Hydrochlorothiazide, ACEI/ARB 4 / / 110.00±23.00 110.00±23.00 134.00±18.00 134.00±18.00 76.00±8.00 76.00±8.00
(2007) 50 mg/d 12.5 mg/d, potassium
chloride 10mEq/d

DOI: 10.1159/000534366
Epstein et al. [50] DKD 182 / 60 Eplerenone, Usual care ACEI/ARB 3 / / / / / / / /
(2006) 50 mg/d
Tofte et al. [51] DKD 209 63 70 Spironolactone, Usual care General therapy 30 / / 81.00±15.00 82.00±19.00 135.00±12.00 134.00±12.00 79.00±9.00 79.00±9.00
(2020) 25 mg/d
Beldhuis et al. CKD 944 74 / Spironolactone, Usual care General therapy 40 / / 45.68±8.85 45.88±8.83 126.56±15.44 126.57±15.43 / /
[52] (2019) 30 mg/d
Chen et al. [53] DKD 105 68 51 Spironolactone, Usual care Irbesartan 18 / / 79.30±13.90 79.10±11.25 / / / /
(2018) 20 mg/d
Chen et al. [53] DKD 101 67 53 Spironolactone, Usual care Irbesartan 18 / / 80.00±13.50 78.70±12.70 / / / /
(2018) 20 mg/d
Srivastava et al. DKD 54 51 54 Spironolactone, Usual care ACEI/ARB 12 1,094.00±1,088.28 917.00±922.58 / / 135.00±11.00 138.00±15.00 71.00±9.00 75.00±9.00
[54] (2016) 25 mg/d
Kato et al. [55] DKD 52 60 71 Spironolactone, Usual care ACEI/ARB 2 702.10±728.40 511.30±450.10 / / 137.30±16.30 131.30±13.00 76.80±12.20 77.60±8.80
(2015) 25 mg/d
Momeni et al. DKD 40 56 / Spironolactone, Hydrochlorothiazide, General therapy 3 / / 90.70±24.60 87.38±22.00 132.80±12.80 133.50±13.20 84.30±5.40 84.00±7.40
[35] (2015) 50 mg/d 25 mg/d
Momeni et al. DKD 40 57 / Spironolactone, Usual care Hydrochlorothiazide 3 / / 86.20±25.00 87.38±22.00 133.50±14.50 133.50±13.20 84.00±9.40 84.00±7.40
[35] (2015) 50 mg/d
Moras CKD 42 56 67 Spironolactone, Hydrochlorothiazide, ACEI/ARB 6 / / 66.00±26.00 66.00±25.00 130.00±18.00 129.00±18.00 76.00±13.00 75.00±12.00
(2015) [56] 25 mg/d 50 mg/d
Moras et al. [56] CKD 42 56 67 Spironolactone, Hydrochlorothiazide, ACEI/ARB 6 / / 66.00±26.00 64.00±24.00 130.00±18.00 128.00±20.00 76.00±13.00 74.00±12.00
(2015) 25 mg/d 50 mg/d, Amiloride,
5 mg/d
Van Buren et al. DKD 53 52 49 Spironolactone, Losartan, 100 mg/d ACEI/ARB 12 1,094.00±1,076.35 897.00±934.51 51.40±34.07 64.80±34.73 135.00±11.00 143.00±15.00 71.00±9.00 75.00±9.00
[57] (2014) 25 mg/d

5
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 6
Table 1 (continued)

Study Disease Patients, Age, Malea Intervention Follow-up UACR, mg/g eGFR, mL/min/1.73 m2 SBP, mm Hg DBP, mm Hg
n years duration,
months
experimental control group background therapy experimental control group experimental control experimental control experimental control
group group group group group group group group

Van Buren et al. DKD 54 51 46 Spironolactone, Usual care ACEI/ARB 12 1,094.00±1,056.23 917.00±905.34 51.40±33.43 73.00±38.76 135.00±11.00 138.00±15.00 71.00±9.00 75.00±9.00
[57] (2014) 25 mg/d
Esteghamati DKD 136 58 67 Spironolactone, Enalapri, 30–40 mg/d ACEI/ARB 18 / / 73.75±16.78 69.13±19.69 134.27±18.12 140.08±18.67 82.26±8.54 83.17±10.29
et al. [58] (2013) 25 mg/d
Wang et al. [59] CKD 208 34 57 Spironolactone, Usual care ACEI/ARB 4 / / 65.77±22.21 66.45±24.34 119.30±13.50 121.10±13.70 72.20±11.60 68.20±11.10
(2013) 20 mg/d
Nielsen et al. [60] DKD 69 53 77 Spironolactone, Usual care ACEI/ARB 4 / / / / / / / /
(2013) 25 mg
Ziaee et al. [61] DKD 60 53 62 Spironolactone, Usual care ACEI/ARB 3 126.30±69.36 119.00±66.86 79.84±18.05 82.55±19.18 127.24±12.50 124.19±12.85 79.31±8.42 75.96±8.60
(2013) 25 mg
Hase et al. [39] DKD 36 64 67 Spironolactone, Trichlormethiazide, ACEI/ARB 6 605.60±703.82 582.60±587.96 61.60±23.90 63.40±17.00 149.00±20.00 146.00±10.00 79.00±14.00 79.00±11.00
(2013) 25–50 mg 2 mg/d

Am J Nephrol
Pitt et al. [42] CKD 132 73 83 Spironolactone, Usual care General therapy 4 24.10±4.60 22.20±5.60 46.80±10.30 46.90±8.20 / / / /
(2013) 25–50 mg/d
Nielsen et al. [62] DKD 21 58 67 Spironolactone, Usual care ACEI/ARB 2 / / / / / / / /
(2012) 25 mg/d
Edwards et al. CKD 112 54 58 Spironolactone, Usual care ACEI/ARB 10 107.47±394.80 92.76±547.51 49.00±12.00 53.00±11.00 130.00±16.00 130.00±19.00 77.00±10.00 77.00±10.00

DOI: 10.1159/000534366
[63] (2012) 25 mg/d
Abolghasmi and CKD 41 50 54 Spironolactone, Usual care General therapy 3
Taziki [64] (2011) 25–50 mg/d
Zheng et al. [65] DKD 40 58 55 Spironolactone, Usual care ACEI/ARB 3 / / / / / / / /
(2011) 20 mg/d
Hammer et al. CKD 112 54 58 Spironolactone, Usual care ACEI/ARB 9 156.64±427.68 72.16±425.92 49.00±12.00 53.00±12.30 124.00±11.00 125.00±12.00 76.00±8.00 77.00±9.00
[66] (2010) 25 mg/d
Guney et al. [67] CKD 30 43 57 Spironolactone, Usual care ACEI/ARB 6 / / 63.02±22.71 56.28±35.59 118.80±15.70 115.80±10.60 72.50±9.70 72.90±7.50
(2009) 25 mg/d
Mehdi et al. [68] DKD 54 51 46 Spironolactone, Usual care ACEI/ARB 13 1,094.00±1,088.28 917.00±922.58 51.40±32.48 73.00±37.67 135.00±11.00 138.00±15.00 71.00±9.00 75.00±9.00
(2009) 25 mg/d
Preston et al. CKD 18 53 78 Spironolactone, Usual care ACEI/ARB 3 / / 45.15±14.44 112.10±13.04 141.44±16.20 117.22±9.17 81.55±10.17 74.16±7.13
[69] (2009) 25 mg/d
Furumatsu et al. CKD 32 52 59 Spironolactone, Trichlormethiazide, ACEI/ARB 12 / / 91.80±11.80 68.90±7.80 126.40±11.20 129.60±10.00 79.10±8.80 79.40±8.80
[37] (2008) 25 mg/d 1 mg/d or furosemide,
10 mg/d
Saklayen et al. DKD 24 / 100 Spironolactone, Usual care ACEI/ARB 7 / / 61.91±23.40 54.44±20.09 153.64±25.95 154.52±21.17 79.56±12.23 79.74±12.85
[70] (2008) 25 mg/d
Tylicki et al. [71] CKD 18 42 61 Spironolactone, Usual care ACEI and ARB 2 / / 107.80±51.84 107.80±51.84 115.28±11.84 115.28±11.84 73.83±7.67 73.83±7.67
(2008) 25 mg/d
van den DKD 59 / 56 Spironolactone, Usual care ACEI/ARB 3 / / / / 144.00±17.00 148.00±13.00 80.00±10.00 82.00±8.00
Meiracker et al. 25–50 mg/d
[72] (2006)
Bianchi et al. [73] CKD 165 55 64 Spironolactone, Usual care ACEI/ARB 12 / / 62.40±21.87 62.20±19.02 132.90±7.29 131.60±5.43 78.50±4.56 78.10±3.62
(2006) 25 mg/d
Schjoedt et al. DKD 20 / 85 Spironolactone, Usual care General therapy 2 / / / / / / / /
[74] (2006) 25 mg/d
Ogawa et al. [38] DKD 30 63 / Spironolactone, Furosemide 20 mg/d ACEI/ARB 12 287.00±37.00 269.00±69.00 70.50±14.50 69.80±11.70 154.60±10.10 156.80±9.80 83.10±6.80 86.80±7.90
(2006) 25 mg/d
Chrysostomou CKD 20 63 70 Spironolactone, Usual care ACEI and ARB 3 / / 59.40±19.44 81.60±55.10 141.00±12.90 133.00±19.50 76.00±10.50 79.50±8.60
et al. [75] (2006) 25 mg/d
Chrysostomou CKD 21 56 67 Spironolactone, Usual care ACEI and ARB 3 / / 57.60±27.58 59.70±28.26 130.00±10.20 132.00±11.40 75.50±6.10 79.50±9.00
et al. [75] (2006) 25 mg/d
Takebayashi DKD 37 / / Spironolactone, Amiloride, 2.5 mg/d General therapy 3 / / / / 135.30±8.10 137.60±8.90 71.70±5.70 74.20±8.90
et al. [30] (2006) 50 mg/d
Schjoedt et al. DKD 22 45 75 Spironolactone, Usual care ACEI/ARB 2 / / / / / / / /
[76] (2005) 25 mg/d
Rossing et al. DKD 21 58 85 Spironolactone, Usual care General therapy 4 / / / / / / / /
[77] (2005) 25 mg/d

Continuous variables are expressed as mean ± standard deviation. UACR, urinary albumin-to-creatinine ratio; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; DKD, diabetic kidney disease; CKD, chronic kidney disease; ACEI, angiotensin
converting enzyme inhibitor; ARB, angiotensin receptor blockers. aPresented as percentage.

Shao/Liu/Zhang/Pan/Zhu/Yu/Yu/Zhu
Yuan/Gao/Lin/Liu/Shen/Zou/Wang/Shen/
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 Downloaded from http://karger.com/ajn/article-pdf/doi/10.1159/000534366/4048477/000534366.pdf by The Library of Nanjing Medical University user on 19 November 2023
Fig. 2. Effects of MRAs on UACR in CKD patients by different MRAs. UACR, urinary albumin-to-creatinine
ratio (expressed in mg/g); WMD, weighted mean difference; MRAs, mineralocorticoid receptor antagonists;
CKD, chronic kidney disease; DKD, diabetic kidney disease.

Effects on Cardiovascular Events Adverse Effects

Eight trials assessed 16,014 patients with 2,124 CVEs.
MRAs significantly reduced the CVE risk (8 trials, RR,
0.84, 95% CI, 0.77–0.92) without significant heterogeneity
among various MRAs (p for interaction = 0.06) (shown in
online suppl. Fig. 8).
Effects on All-Cause Mortality
Five trials included 14,341 participants reported 1,256
death events. MRAs had a trend to decrease all-cause
mortality compared with the control group (5 trials, RR,
0.90, 95% CI, 0.81–1.00). There was a tendency of re-
duction in all-cause mortality by finerenone therapy (2
trials, RR, 0.90, 95% CI, 0.80–1.00) (shown in online
suppl. Fig. 9).
Overall, MRAs significantly increased the incidence
of hyperkalemia (31 trials, RR, 2.04, 95% CI,
1.73–2.40) without significant heterogeneity among
different MRAs (p for interaction = 0.34). MRAs
significantly increased the incidence of hypotension (7
trials; RR, 1.80, 95% CI, 1.41–2.31), decreased the
incidence of peripheral edema (3 trials, RR, 0.65, 95%
CI, 0.56–0.75), whereas they did not significantly in-
crease the incidence of acute kidney injury (AKI) (4
trials, RR, 0.94, 95% CI, 0.79–1.13), reproductive
system disorders (4 trials, RR, 1.23, 95% CI,
0.45–3.37), and breast disorders (10 trials, RR, 1.39,
95% CI, 0.43–4.48) (shown in Table 2). The incidence
of breast disorders was not significantly different

Mineralocorticoid Receptor Antagonists for Am J Nephrol 7

Chronic Kidney Disease DOI: 10.1159/000534366
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(For legend see next page.)

Yuan/Gao/Lin/Liu/Shen/Zou/Wang/Shen/
Shao/Liu/Zhang/Pan/Zhu/Yu/Yu/Zhu
DOI: 10.1159/000534366
Am J Nephrol
8
3
between the male and female participants (gyneco-
mastia: 5 trials, RR, 0.88, 95% CI, 0.42–1.85; breast
disorders in females: 2 trials, RR, 0.17, 95% CI,
0.02–1.40; p for interaction = 0.16).
Publication Bias
There was significant evidence of publication bias for
chronic kidney failure events (Egger’s test, p = 0.04),
whereas there was no significant publication bias in the
other outcomes (Egger’s test, p > 0.05) (shown in online
suppl. Fig. 10).
Subgroup Analyses
Subgroup analyses were performed to clarify the effects
of MRAs in the relationship with ACEI/ARB, in different
CKD diseases, and to compare the effects between ste-
roidal and nonsteroidal MRA agents by the stratum of age
(cutoff point at 60 years old), eGFR (cutoff point at
60 mL/min/1.73 m2), UACR (cutoff point at 300 mg/g),
sample size (cutoff point at 30 participants), and risk of
bias (high vs. low/medium risk of bias) (shown in Fig. 4).
Overall, MRAs significantly reduced eGFR compared
with placebo (32 trials, WMD, −3.04 mL/min/1.73 m2,
95% CI, −4.12 to −1.96 mL/min/1.73 m2). MRAs sig-
nificantly reduced UACR (9 trials, WMD, −90.32 mg/g,
95% CI, −149.44 to −31.20 mg/g) and eGFR (27 trials,
WMD, −3.35 mL/min/1.73 m2, 95% CI, −4.52
to −2.18 mL/min/1.73 m2) compared with placebo, with a
background of ACEi/ARB. MRAs did not significantly
change eGFR compared with placebo, without the
background of ACEi/ARB (5 trials, WMD, −0.72 mL/
min/1.73 m2, 95% CI, −3.60 to 2.17 mL/min/1.73 m2).
MRAs alone did not significantly change UACR (1 trial,
WMD, −9.26 mg/g, 95% CI, −31.99 to 13.47 mg/g) and
eGFR (2 trials, WMD, 0.72 mL/min/1.73 m2, 95%
CI, −3.63–5.07 mL/min/1.73 m2) compared with ACEI/
ARB alone.
Nonsteroidal MRAs more significantly reduced UACR
(nonsteroidal MRAs, 3 trials, WMD, −189.79, 95%
CI, −344.42 to −35.16 mg/g; steroidal MRAs, 7 trials,
WMD, −41.06, 95% CI, −71.06 to −11.06 mg/g, p for
interaction = 0.06) and eGFR (nonsteroidal MRAs, 5
trials, WMD, −4.82 mL/min/1.73 m2, 95% CI, −6.79
to −2.84 mL/min/1.73 m2; steroidal MRAs, 31 trials,
WMD, −0.49 mL/min/1.73 m2, 95% CI, −2.17 to 1.19 mL/
min/1.73 m2; p for interaction = 0.001) compared with
steroidal MRAs.
Fig. 3. Effects of MRAs on eGFR in CKD patients by different MRAs. eGFR, estimated glomerular filtration rate
(expressed in mL/min/1.73 m2); WMD, weighted mean difference; MRAs, mineralocorticoid receptor antag-
onists; CKD, chronic kidney disease; DKD, diabetic kidney disease.
Mineralocorticoid Receptor Antagonists for
Chronic Kidney Disease
Compared with the control group, MRAs significantly
decreased UACR in DKD patients (6 trials,
WMD, −114.41 mg/g, 95% CI, −178.40 to −50.41 mg/g)
and UPE in non-diabetes CKD patients (1 trials,
WMD, −0.70 g, 95% CI, −1.14 to −0.26 g), whereas they
did not significantly change UACR in non-diabetes CKD
patients (4 trials, WMD, −21.26 mg/g, 95% CI, −42.66 to
0.15 mg/g). MRAs significantly decreased eGFR in DKD
patients (20 trials, WMD, −3.32 mL/min/1.73 m2, 95%
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CI, −4.63 to −2.01 mL/min/1.73 m2), whereas they did
not significantly change GFR in non-diabetes CKD
(8 trials, WMD, 1.11 mL/min/1.73 m2 , 95%
CI, −6.38–8.60 mL/min/1.73 m2 ) and unspecified
CKD patients (8 trials, WMD, −0.82 mL/min/1.73 m2 ,
95% CI, −2.35 to 0.71 mL/min/1.73 m2) (p for
interaction = 0.04).
MRAs more significantly reduced both UACR and
eGFR in the elder patients (UACR: 4 trials,
WMD, −189.38 mg/g, 95% CI, −305.83 to −72.93 mg/g;
eGFR: 11 trials, WMD, −3.42 mL/min/1.73 m2, 95%
CI, −4.91 to −1.93 mL/min/1.73 m2) compared with the
young patients (UACR: 6 trials, WMD, −24.20 mg/g, 95%
CI, −39.60 to −8.80 mg/g; eGFR: 22 trials,
WMD, −0.20 mL/min/1.73 m2, 95% CI, −2.93 to 2.52 mL/
min/1.73 m2) (p for interaction for UACR = 0.006, p for
interaction for eGFR = 0.04).
MRAs significantly reduced more UACR in the pa-
tients with high baseline UACR levels (3 trials,
WMD, −256.86 mg/g, 95% CI, −425.02 to −88.71 mg/g)
compared with those with low baseline UACR levels (7
trials, WMD, −43.63 mg/g, 95% CI, −70.91 to −16.35 mg/g)
(p for interaction = 0.01). There was no significant difference
in the change of eGFR between the patients with high
baseline UACR levels and those with low baseline UACR
levels (p for interaction = 0.37).
There was no significant difference in the change of
UACR between the trials with high risk of bias and those
with low/medium risk of bias (p for interaction for
UACR = 0.38). MRAs reduced eGFR more in the trials
with low/medium risk of bias (17 trials, WMD, −3.67 mL/
min/1.73 m2, 95% CI, −4.85 to −2.49 mL/min/1.73 m2)
compared with those with high risk of bias (19 trials,
WMD, 1.45 mL/min/1.73 m2, 95% CI, −1.41–4.31 mL/
min/1.73 m2) (p for interaction = 0.001).
There was no significant difference in the change of
UACR and eGFR by MRAs between the patients with
high eGFR and those with low eGFR, and between the
Am J Nephrol 9
DOI: 10.1159/000534366
 trials with a large sample size and those with a small
sample size (shown in Fig. 4). There was no significant
interaction

heterogeneity among the nonsteroidal MRAs and ste-

p for

0.91

0.34

0.80

0.28

0.99

0.41

0.67
roidal MRAs in the incidence of hyperkalemia (p for

<0.001

<0.001

<0.001
value

0.52

0.69

0.58

0.67
interaction = 0.65) and AKI (p for interaction = 0.91).
p

(95% CI)

Nonsteroidal MRAs (2 trials, RR, 0.66, 95% CI, 0.57–0.75)

23.17)

60.78)

25.67)
(1.83,

(1.12,

(0.10,

(1.26,

(0.35,
3.87)

4.04)
2.66

5.10

2.52

5.68

1.18
RR

but not steroidal MRAs (1 trial, RR, 0.20, 95% CI,

36/1,193
control

0/215

0/118

0/328

4/179
0.02–1.68) significantly reduced the incidence of pe-
spironolactone

ripheral edema. Steroidal MRAs (8 trials, RR, 5.68, 95%

experimental

Downloaded from http://karger.com/ajn/article-pdf/doi/10.1159/000534366/4048477/000534366.pdf by The Library of Nanjing Medical University user on 19 November 2023
148/1,204

CI, 1.26–25.67) but not nonsteroidal MRAs (2 trials, RR,

11/325
9/212

1/130

5/174
0.52, 95% CI, 0.22–1.22) increased the incidence of breast
(95% CI)

disorders (shown in online suppl. Fig. 11).

71.78)

40.89)

72.69)
(0.13,

(1.10,

(0.55,

(0.02,

(0.12,
2.33)

1.68)
3.00

1.60

4.74

0.20

3.00
RR

/
139/2119
control

Meta-Regression Analyses
0/46

0/92

5/91

0/91

0/91

Univariate meta-regression analyses suggested that for

experimental
eplerenone

254/2,505

every 1 mg/g increase in the baseline UACR, UACR

1/46

4/92

1/91

1/91

0/91

reduction was improved by 0.3 mg/g by the MRAs

therapy (95% CI, −0.4 to −0.2 mg/g; p < 0.001) (shown in
(0.48,
(95%

3.51)
1.30
CI)
RR

Table 3). For every 1 mL/min/1.73 m2 increase in the

control

0/57

5/57

baseline eGFR, UACR reduction was decreased by

ocedurenone

experimental

6.9 mg/d by the MRAs therapy (95% CI, 1.4–12.4 mg/g;

12/105

p = 0.02). With every year increase in the baseline age, the

0/105

effects of MRAs on UACR decreased by 11.8 mg/g (95%

(95% CI)

64.92)

CI, −22.3 to −1.2 mg/g; p = 0.03). For every 1 mm Hg

(0.20,
3.63
RR

increase in the baseline SBP, UACR reduction was im-

control

0/72

proved by 15.1 mg/g (95% CI, −28.6 to −1.52 mg/g; p =

experimental
apararenone

0.04) by the spironolactone therapy (shown in online

5/220

suppl. Table 3). There was no significant association

among the changes of different parameters in the meta-
(1.79,
(95%

8.88)
3.98
CI)
RR

regression analyses for the intervention by eplerenone/

finerenone (shown in online suppl. Tables 4–5).
control

7/302
Table 2. Adverse effects of MRAs as compared with the control

Values for events are given as n/N. MRAs, mineralocorticoid receptor antagonists; RR, relative risk; CI, confidence interval.
experimental
esaxerenone

Sensitivity Analyses
35/369

The effects of MRAs on the outcomes (shown in online

suppl. Fig. 12–18) and the results of subgroup analyses
(0.78,

(1.83,

(1.34,

(0.57,

(0.32,

(0.22,

(0.29,

(0.02,
(95%

1.12)

2.26)

2.23)

0.75)

3.10)

1.22)

1.89)

1.40)
0.94

2.03

1.73

0.66

1.00

0.52

0.74

0.17
CI)
RR

(shown in online suppl. Fig. 19) did not change signifi-

234/6,489

449/6,660

584/6,489
90/3,723

16/6,489

11/6,489

cantly after excluding the five trials employing multiple

5/6,491
control

6/2831

MRA dose groups [60, 65, 69, 74, 28].

experimental
finerenone

220/6,510

919/6,955

157/3,750

384/6,510

8/6,510

8/6,510

0/6,513
6/2827

Discussion
(0.79,

(1.73,

(1.41,

(0.56,

(0.45,

(0.43,

(0.42,

(0.02,
(95%

1.13)

2.40)

2.31)

0.75)

3.37)

4.48)

1.85)

1.40)
0.94

2.04

1.80

0.65

1.23

1.39

0.88

0.17
CI)
RR

641/10,460
234/6,592

589/6,580
90/4,030

16/6,908

15/6,668

The present study consolidated data from extensive

6/3,040

5/6,491
control

trials of MRAs for CKD patients, indicating that in the

experimental

1,385/11,463

CKD patients, MRAs, particularly in combination with

221/6,661

170/4,054

385/6,601

19/6,926

13/6,684
8/3,048

0/6,513
overall
Events

ACEI/ARB, reduced albuminuria/proteinuria, eGFR,

and the incidence of chronic renal failure, cardiovas-
Studies,

cular, and peripheral edema events, whereas increasing

31

10
n

the incidence of hyperkalemia and hypotension

system disorders

Breast disorders

Breast disorders
Adverse events

Gynecomastia
Hyperkalemia
Acute kidney

Reproductive
Hypotension

without the augment of acute kidney injury events.

in females
Peripheral
edema
injury

Nonsteroidal MRAs were superior in the reduction of

10 Am J Nephrol Yuan/Gao/Lin/Liu/Shen/Zou/Wang/Shen/
DOI: 10.1159/000534366 Shao/Liu/Zhang/Pan/Zhu/Yu/Yu/Zhu

a b
Fig. 4. Subgroup analyses for UACR and eGFR. a Subgroup an-
alyses of MRAs for UACR. b Subgroup analyses of MRAs for
eGFR. Subgroup analyses were performed in the relationship with
ACEi/ARB, in different CKD diseases, and to compare the effects
between steroidal and nonsteroidal MRA agents by the stratum of
age (cutoff point at 60 years old), eGFR (cutoff point at 60 mL/
min/1.73 m2), UACR (cutoff point at 300 mg/g), sample size
(cutoff point at 30 participants), and risk of bias (high vs. low/
more albuminuria with fewer peripheral edema events
and without the augment of breast disorder events.
The present study showed that MRAs significantly
reduced UACR compared with placebo with background
of ACEI/ARB, which may be related to the hemodynamic
effects, the preservation of the glycocalyx and modulation
of matrix metalloproteinase (MMP) activity by MRAs,
and the protective effects for podocyte via the inhibition
of Rac1 activity of MRAs [78, 79]. Nonsteroidal MRAs,
with a high selectivity for MR, were superior to steroidal
MRAs in the reduction of UACR. UACR was decreased
more significantly in the DKD patients compared with
the non-diabetes CKD patients, which may be due to the
usage of predominantly nonsteroidal MRAs in the in-
cluded DKD trials [80]. There was an inconsistency that
MRAs significantly reduced UPE but not UACR in the
non-diabetes CKD patients; this may be explained by the
fact that 2 of 4 trials for the assessment of UACR in the
non-diabetes CKD patients adopted eplerenone (the
other two used spironolactone), whose effect was weaker
than that of spironolactone. The effects of MRAs on
UACR were increased by the increase in baseline age,
which might be related to lower plasma aldosterone levels
Mineralocorticoid Receptor Antagonists for
Chronic Kidney Disease
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medium risk of bias). UACR, urinary albumin-to-creatinine ratio
(expressed in mg/g); eGFR, estimated glomerular filtration rate
(expressed in mL/min/1.73 m2); WMD, weighted mean difference;
MRAs, mineralocorticoid receptor antagonists; RAASi, renin-
angiotensin-aldosterone system inhibitors; ACEI, angiotensin-
converting enzyme inhibitor; ARB, angiotensin receptor
blocker; CKD, chronic kidney disease; DKD, diabetic kidney
disease.
in the elder patients [81]. The meta-regression analyses
suggested the UACR reduction by MRAs was reduced
with the increase of eGFR, which may be due to the more
aldosterone excretion in the patients with higher eGFR
levels [82]. Spironolactone has a more pronounced effect
on the UACR reduction in the higher baseline SBP pa-
tients, which might be due to its effects in reduction of
aldosterone with its attendant renal effects on sodium and
fluid retention in hypertensive patients [83].
The present study indicated that MRAs decreased
eGFR in CKD patients and reduced chronic kidney
failure events. It has been demonstrated that MRAs in-
tervention may cause an initial acute reduction in eGFR
and then stabilization of eGFR in the long run [27, 43, 51,
55] as the effects by ACEI/ARB intervention [84–86].
MRAs reduce intraglomerular pressure via impaired
tubuloglomerular feedback to inhibit proteinuria and
protect the kidney in the long term [87]. This hemo-
dynamic effect was demonstrated by the recovery of
eGFR after discontinuation of MRAs [26, 33]. In addition,
MRAs may also alleviate renal injury by anti-
inflammatory, antifibrotic, and antioxidative effects
[88]. The reduction of eGFR by MRAs in the present
Am J Nephrol 11
DOI: 10.1159/000534366
Table 3. Metaregression analyses in
the association of eGFR, UACR, SBP, Parameters and covariates Coefficient (95% CI) p value
DBP, serum potassium with the other
eGFR, mL/min/1.73 m2
parameters
Baseline UACR, mg/g 0.0001 (−0.0004 to 0.0006) 0.66
Baseline eGFR, mL/min/1.73 m2 0.07 (−0.09 to 0.23) 0.40
Baseline SBP, mm Hg 0.01 (−0.08 to 0.10) 0.86
Baseline DBP, mm Hg 0.03 (−0.13 to 0.19) 0.70
Age, years −0.12 (−0.31 to 0.06) 0.17
Background therapy
ACEi/ARB 0.6 (−4.2 to 5.4) 0.81

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UACR, mg/g
Baseline UACR, mg/g −0.3 (−0.4 to −0.2) <0.001
Baseline eGFR, mL/min/1.73 m2 6.9 (1.4–12.4) 0.02
Baseline SBP, mm Hg −3.8 (−15.6 to 8.0) 0.48
Baseline DBP, mm Hg 9.22 (−5.44 to 23.89) 0.19
Age, years −11.8 (−22.3 to −1.2) 0.03
Background therapy
ACEi/ARB −189 (−464 to 86) 0.44
SBP, mm Hg
Baseline UACR, mg/g −0.001 (−0.005 to 0.003) 0.58
Baseline eGFR, mL/min/1.73 m2 0.07 (0.01–0.14) 0.06
Baseline SBP, mm Hg −0.05 (−0.13 to 0.04) 0.26
Baseline DBP, mm Hg −0.03 (−0.18 to 0.11) 0.65
Age, years 0.03 (−0.21 to 0.15) 0.73
Background therapy
ACEi/ARB 3.92 (−1.02 to 8.87) 0.12
DBP, mm Hg
Baseline UACR, mg/g −0.001 (−0.004 to 0.001) 0.34
Baseline eGFR, mL/min/1.73 m2 −0.04 (−0.02 to 0.10) 0.16
Baseline SBP, mm Hg −0.01 (−0.05 to 0.03) 0.51
Baseline DBP, mm Hg −0.01 (−0.07 to 0.06) 0.86
Age, years −0.05 (−0.14 to 0.03) 0.20
Background therapy
ACEi/ARB 1.6 (−1.0 to 4.1) 0.22
Serum potassium, mmol/L
Baseline UACR, mg/g 0.0001 (−0.0001 to 0.0002) 0.36
Baseline eGFR, mL/min/1.73 m2 −0.003 (−0.006 to 0.001) 0.15
Baseline SBP, mm Hg −0.002 (−0.008 to 0.003) 0.41
Baseline DBP, mm Hg −0.001 (−0.002 to 0.001) 0.44
Age, years 0.005 (−0.001 to 0.010) 0.11
Background therapy
ACEi/ARB 0.07 (−0.07 to 0.20) 0.34

There were too few studies of esaxerenone and apararenone to conduct meta-
regression analyses. eGFR, estimated glomerular filtration rate; UACR, urinary albumin-
to-creatinine ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; ACEi,
angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blocker; CI,
confidence interval.

study may be associated with the short period of follow-
up (≥3 years in only 4 of 36 trials) in the included
trials, reflecting the initial reduction in eGFR by
MRAs. It has been demonstrated that 3-year total
eGFR slope as the surrogate endpoint can predict
kidney benefit, but 2-year total eGFR did not, which
related to the fact that acute eGFR reduction has a
greater impact on the computation of total slope when
the total slope is computed over shorter time intervals
[89]. Here, MRAs significantly reduced chronic renal
failure events by pooling the four trials with a relative
long-term follow-up, suggesting the protective effects
of MRAs for CKD patients in the long term. Non-
steroidal MRAs, with a higher selectivity for MR, can

12 Am J Nephrol Yuan/Gao/Lin/Liu/Shen/Zou/Wang/Shen/
DOI: 10.1159/000534366 Shao/Liu/Zhang/Pan/Zhu/Yu/Yu/Zhu
reduce eGFR more compared with steroidal MRAs to
reduce intraglomerular pressure more for glomerular
protection. Finerenone, as the nonsteroidal MRA, can
more significantly reduce chronic kidney failure
events. Subgroup analyses indicated that the elder
patients receiving mainly nonsteroidal MRAs of the
included trial presented with more reduction of eGFR.
The funnel plot of chronic kidney failure events
exhibited noticeable asymmetry, suggesting publica-
tion bias that some negative results were not pub-
lished. It might also be associated with the limited
number of included trials with the outcome of chronic
kidney failure.
The dual blockade of ACEI and ARB in CKD patients
could lower blood pressure and albuminuria more sub-
stantially, whereas reduce the glomerular perfusion to
cause AKI [90, 91]. The present study indicated that
MRAs in combination with ACEI/ARB significantly re-
duced UACR and high glomerular hyperfiltration status
without augment of AKI events. This might be related to
the inhibition of “aldosterone breakthrough” and Rac1-
induced oxidative stress in smooth muscle cells by adding
MRAs [92], showing a superiority of the combination of
MRAs and ACEI/ARB over the combination of ACEI and
ARB. MRAs could significantly reduce the incidence of
CVE and marginally reduce all-cause mortality, which
may be associated with their anti-inflammatory and
antifibrotic effects [13, 93].
The present study suggested that MRAs increase
blood potassium levels and the risk of hyperkalemia.
Here, no significant difference existed between ste-
roidal MRAs and nonsteroidal MRAs in the incidence
of hyperkalemia, which may be explained by including
the trials of steroidal MRAs with a high MR selectivity
of eplerenone with up to 40-fold less potency than
spironolactone for MR activation with a low risk of
hyperkalemia [20, 94], as well as the relative high risk
of hyperkalemia by nonsteroidal MRAs of esaxer-
enone. Our meta-analysis found that apararenone and
ocedurenone did not significantly increase the risk of
hyperkalemia, and the risk of hyperkalemia of finer-
enone was lower than that of spironolactone. Routine
potassium monitoring and hyperkalemia management
strategies might minimize the impact of hyperkalemia,
thus providing a basis for the clinical use of nonste-
roidal MRAs [95]. Embracing these innovative agents
not only offered the promise of safeguarding against
hyperkalemia but also retained the profound thera-
peutic advantages inherently associated with MRAs.
The effects of MRAs on the reduction of SBP decreased
with the increase of eGFR, which may be due to the
Mineralocorticoid Receptor Antagonists for
Chronic Kidney Disease
accumulation of plasma aldosterone with GFR decline
[96, 97]. The risk of hypotension induced by finer-
enone therapy was far lower than that by the inter-
vention of eplerenone or spironolactone. Nonsteroidal
MRAs, particularly finerenone, did not increase the
risk of breast diseases. These may be associated with
the high potency and selectivity of finerenone for MR
and the low half-life of finerenone [20, 98].
The strengths of this work included its comprehensive
Downloaded from http://karger.com/ajn/article-pdf/doi/10.1159/000534366/4048477/000534366.pdf by The Library of Nanjing Medical University user on 19 November 2023
and inclusive approach, robust methodology, and en-
rolling many trials with large populations. The limitations
are the poor quality of some of the included trials.
Conclusions
In the CKD patients, MRAs, particularly in com-
bination with ACEI/ARB, reduced albuminuria/
proteinuria, eGFR, and the incidence of chronic re-
nal failure, and cardiovascular and peripheral edema
events, whereas increasing the incidence of hyper-
kalemia and hypotension, without the augment of
acute kidney injury events. Nonsteroidal MRAs were
superior in the reduction of more albuminuria with
fewer peripheral edema events and without the aug-
ment of breast disorder events.
Acknowledgments
We thank Dr. Pitt Bertram and Bakris George L. for providing
us with additional data not shown in the published paper.
Statement of Ethics
An ethics statement is not applicable because this study is based
exclusively on published literature.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This research was funded by grants from the State Adminis-
tration of Traditional Chinese Medicine and Zhejiang Province
Co-construction Project (No. 2023017961); the project of Zhejiang
Traditional Chinese Medicine Administration (No. 2022ZA122);
and the project of Basic Public Welfare Research Program of
Zhejiang Province (No. LGF18H050005).
Am J Nephrol 13
DOI: 10.1159/000534366
 Author Contributions
Study concept and design: Bin Zhu, Chen-Yi Yuan, and Yuan-
Cheng Gao; literature retrieval and data extraction: Chen-Yi Yuan,
Yuan-Cheng Gao, and Bin Zhu; statistical analysis: Chen-Yi Yuan,
Yuan-Cheng Gao, Bin Zhu, Yi Lin, and Lin Liu; interpretation of
data: Chen-Yi Yuan, Yuan-cheng Gao, Bin Zhu, Xiao-Gang Shen,
Wen-Li Zou, and Yue-Ming Liu; and quality assessment: Chen-Yi
Yuan, Yuan-Cheng Gao, Bin Zhu, Min-Min Wang, Quan-Quan
Shen, Li-Na Shao, Jia-Wei Zhang, Zhi-Hui Pan, Yan Zhu, Jing-
Ting Yu, and Xu-Guang Yu. Each author contributed important
intellectual content during manuscript drafting or revision and
gave final approval of the version to be submitted.
Data Availability Statement
All data generated or analyzed during this study are included in
this article and its online supplementary material. Further in-
quiries can be directed to the corresponding author.

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References

1 Johansen KL, Chertow GM, Gilbertson DT,
Ishani A, Israni A, Ku E, et al. US renal data
system 2022 annual data report: epidemiology
of kidney disease in the United States. Am
J Kidney Dis. 2023 Mar;81(3 Suppl 1):A8–11.
2 Kovesdy CP. Epidemiology of chronic kidney
disease: an update 2022. Kidney Int Suppl.
2022 Apr;12(1):7–11.
3 Li H, Lu W, Wang A, Jiang H, Lyu J.
Changing epidemiology of chronic kidney
disease as a result of type 2 diabetes mellitus
from 1990 to 2017: estimates from Global
Burden of Disease 2017. J Diabetes Investig.
2021 Mar;12(3):346–56.
4 Kearney PM, Whelton M, Reynolds K,
Muntner P, Whelton PK, He J. Global burden
of hypertension: analysis of worldwide data.
Lancet. 2005;365(9455):217–23.
5 Umanath K, Lewis JB, LewisJulia B. Update
on diabetic nephropathy: core curriculum
2018. Am J Kidney Dis. 2018;71(6):884–95.
6 Kidney Disease Improving Global Outcomes
KDIGO Diabetes Work Group. KDIGO 2020
clinical practice guideline for diabetes man-
agement in chronic kidney disease. Kidney
Int. 2020;98(4S):S1–115.
7 American Diabetes Association. 11. Micro-
vascular complications and foot care: stan-
dards of medical care in diabetes-2020. Di-
abetes Care. 2020 Jan;43(Suppl 1):S135–51.
8 Joffe HV, Adler GK. Effect of aldosterone and
mineralocorticoid receptor blockade on vascular
inflammation. Heart Fail Rev. 2005 Jan;
10(1):31–7.
9 Patel V, Joharapurkar A, Jain M. Role of
mineralocorticoid receptor antagonists in
kidney diseases. Drug Dev Res. 2021 May;
82(3):341–63.
10 Schwenk MH, Hirsch JS, Bomback AS. Al-
dosterone blockade in CKD: emphasis on
pharmacology. Adv Chronic Kidney Dis.
2015 Mar;22(2):123–32.
11 Perkovic V, Jardine MJ, Neal B, Bompoint S,
Heerspink HJL, Charytan DM, et al. Cana-
gliflozin and renal outcomes in type 2 dia-
betes and nephropathy. N Engl J Med. 2019
Jun 13;380(24):2295–306.
12 Oshima M, Neuen BL, Li J, Perkovic V,
Charytan DM, de Zeeuw D, et al. Early change
in albuminuria with canagliflozin predicts
kidney and cardiovascular outcomes: a post hoc
analysis from the CREDENCE trial. J Am Soc
Nephrol. 2020 Dec;31(12):2925–36.
13 Kolkhof P, Jaisser F, Kim SY, Filippatos G,
Nowack C, Pitt B. Steroidal and novel non-
steroidal mineralocorticoid receptor antago-
nists in heart failure and cardiorenal diseases:
comparison at bench and bedside. Handb
Exp Pharmacol. 2017;243:271–305.
14 Epstein M. Aldosterone and mineralocorti-
coid receptor signaling as determinants of
cardiovascular and renal injury: an extraor-
dinary paradigm shift. Am J Nephrol. 2021;
52(3):209–16.
15 Alexandrou ME, Papagianni A, Tsapas A,
Loutradis C, Boutou A, Piperidou A, et al.
Effects of mineralocorticoid receptor antag-
onists in proteinuric kidney disease: a sys-
tematic review and meta-analysis of ran-
domized controlled trials. J Hypertens. 2019
Dec;37(12):2307–24.
16 Takahashi M, Ubukata O, Homma T, Asoh
Y, Honzumi M, Hayashi N, et al. Crystal
structure of the mineralocorticoid receptor
ligand-binding domain in complex with a
potent and selective nonsteroidal blocker,
esaxerenone (CS-3150). FEBS Lett. 2020 May;
594(10):1615–23.
17 Barrera-Chimal J, Kolkhof P, Lima-Posada I,
Joachim A, Rossignol P, Jaisser F. Differen-
tiation between emerging non-steroidal and
established steroidal mineralocorticoid re-
ceptor antagonists: head-to-head compari-
sons of pharmacological and clinical char-
acteristics. Expert Opin Investig Drugs. 2021
Nov;30(11):1141–57.
18 Nakamura T, Kawaguchi A. Phase 1 studies
to define the safety, tolerability, and phar-
macokinetic and pharmacodynamic profiles
of the nonsteroidal mineralocorticoid re-
ceptor antagonist apararenone in healthy
volunteers. Clin Pharmacol Drug Dev. 2021
Apr;10(4):353–65.
19 Bakris GL, Agarwal R, Anker SD, Pitt B,
Ruilope LM, Rossing P, et al. Effect of fi-
nerenone on chronic kidney disease out-
comes in type 2 diabetes. N Engl J Med. 2020
Dec 3;383(23):2219–29.
20 Agarwal R, Kolkhof P, Bakris G, Bauersachs J,
Haller H, Wada T, et al. Steroidal and non-
steroidal mineralocorticoid receptor antago-
nists in cardiorenal medicine. Eur Heart J.
2020;42(2):152–61.
21 Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris
GL, Rossing P, et al. Cardiovascular events with
finerenone in kidney disease and type 2 diabetes.
N Engl J Med. 2021 Dec 9;385(24):2252–63.
22 Jiang X, Zhang Z, Li C, Zhang S, Su Q, Yang S,
et al. Efficacy and safety of non-steroidal
mineralocorticoid receptor antagonists in
patients with chronic kidney disease and type
2 diabetes: a systematic review incorporating
an indirect comparisons meta-analysis. Front
Pharmacol. 2022;13:896947.
23 Vrabel M. Preferred reporting items for sys-
tematic reviews and meta-analyses: the PRIS-
MA statement. Revista Espaola De Nutrición
Humana Y Dietética. 2009;18(3):e123.
24 Higgins JPTTJ, Chandler J, Cumpston M, Li T,
Page MJ, Welch VA. Cochrane handbook for
systematic reviews of interventionsversion 6.3.
Cochrane; 2022 [updated February 2022].
25 DerSimonian R, Laird N. Meta-analysis in
clinical trials revisited. Contemp Clin Trials.
2015 Nov;45(Pt A):139–45.
26 Ito S, Shikata K, Nangaku M, Okuda Y, Sa-
wanobori T. Efficacy and safety of esaxer-
enone (CS-3150) for the treatment of type 2
diabetes with microalbuminuria: a random-
ized, double-blind, placebo-controlled, phase
II trial. Clin J Am Soc Nephrol. 2019 Aug 7;
14(8):1161–72.
27 Ito S, Kashihara N, Shikata K, Nangaku M,
Wada T, Okuda Y, et al. Esaxerenone (CS-3150)
in patients with type 2 diabetes and micro-
albuminuria (ESAX-DN): phase 3 randomized
controlled clinical trial. Clin J Am Soc Nephrol.
2020 Dec 7;15(12):1715–27.
28 Wada T, Inagaki M, Yoshinari T, Terata R,
Totsuka N, Gotou M, et al. Apararenone in
patients with diabetic nephropathy: results of
a randomized, double-blind, placebo-
controlled phase 2 dose-response study and
open-label extension study. Clin Exp Neph-
rol. 2021 Feb;25(2):120–30.
29 Bakris G, Pergola PE, Delgado B, Genov D,
Doliashvili T, Vo N, et al. Effect of KBP-5074
on blood pressure in advanced chronic kid-
ney disease: results of the BLOCK-CKD
study. Hypertension. 2021 Jul;78(1):74–81.

14 Am J Nephrol Yuan/Gao/Lin/Liu/Shen/Zou/Wang/Shen/
DOI: 10.1159/000534366 Shao/Liu/Zhang/Pan/Zhu/Yu/Yu/Zhu
30 Takebayashi K, Matsumoto S, Aso Y, Inukai
T. Aldosterone blockade attenuates urinary
monocyte chemoattractant protein-1 and
oxidative stress in patients with type 2 dia-
betes complicated by diabetic nephropathy.
J Clin Endocrinol Metab. 2006 Jun;91(6):
2214–7.
31 Morales E, Huerta A, Gutiérrez E, Gutiérrez
Solís E, Segura J, Praga M. The anti-
proteinuric effect of the blockage of the renin-
angiotensin-aldosterone system (RAAS) in
obese patients. Which treatment option is the
most effective?. Nefrologia. 2009;29(5):
421–9.
32 El Mokadem M, Abd El Hady Y, Aziz A. A
prospective single-blind randomized trial of
ramipril, eplerenone and their combination
in type 2 diabetic nephropathy. Cardiorenal
Med. 2020;10(6):392–401.
33 Provenzano M, Puchades MJ, Garofalo C,
Jongs N, D’Marco L, Andreucci M, et al.
Albuminuria-lowering effect of dapagliflozin,
eplerenone, and their combination in patients
with chronic kidney disease: a randomized
crossover clinical trial. J Am Soc Nephrol.
2022 Aug;33(8):1569–80.
34 Joffe HV, Kwong RY, Gerhard-Herman MD,
Rice C, Feldman K, Adler GK. Beneficial
effects of eplerenone versus hydrochlorothi-
azide on coronary circulatory function in
patients with diabetes mellitus. J Clin En-
docrinol Metab. 2007 Jul;92(7):2552–8.
35 Momeni A, Behradmanesh MS, Kheiri S,
Karami Horestani M. Evaluation of spi-
ronolactone plus hydrochlorothiazide in re-
ducing proteinuria in type 2 diabetic ne-
phropathy. J Renin Angiotensin Aldosterone
Syst. 2015 Mar;16(1):113–8.
36 Morales E, Caro J, Gutierrez E, Sevillano A,
Auñón P, Fernandez C, et al. Diverse di-
uretics regimens differentially enhance the
antialbuminuric effect of renin-
angiotensin blockers in patients with
chronic kidney disease. Kidney Int. 2015
Dec;88(6):1434–41.
37 Furumatsu Y, Nagasawa Y, Tomida K, Mi-
kami S, Kaneko T, Okada N, et al. Effect of
renin-angiotensin-aldosterone system triple
blockade on non-diabetic renal disease: ad-
dition of an aldosterone blocker, spi-
ronolactone, to combination treatment with
an angiotensin-converting enzyme inhibitor
and angiotensin II receptor blocker. Hyper-
tens Res. 2008 Jan;31(1):59–67.
38 Ogawa S, Takeuchi K, Mori T, Nako K, Ito S.
Spironolactone further reduces urinary al-
bumin excretion and plasma B-type natri-
uretic peptide levels in hypertensive type II
diabetes treated with angiotensin-converting
enzyme inhibitor. Clin Exp Pharmacol
Physiol. 2006;33(5–6):477–9.
39 Hase M, Babazono T, Ujihara N, Uchigata Y.
Comparison of spironolactone and tri-
chlormethiazide as add-on therapy to renin-
angiotensin blockade for reduction of albu-
minuria in diabetic patients. J Diabetes In-
vestig. 2013 May 6;4(3):316–9.
Mineralocorticoid Receptor Antagonists for
Chronic Kidney Disease
40 Katayama S, Yamada D, Nakayama M, Yamada
T, Myoishi M, Kato M, et al. A randomized
controlled study of finerenone versus placebo in
Japanese patients with type 2 diabetes mellitus
and diabetic nephropathy. J Diabetes Compli-
cations. 2017 Apr;31(4):758–65.
41 Bakris GL, Agarwal R, Chan JC, Cooper ME,
Gansevoort RT, Haller H, et al. Effect of fi-
nerenone on albuminuria in patients with
diabetic nephropathy: a randomized clinical
trial. JAMA. 2015 Sep 1;314(9):884–94.
42 Pitt B, Kober L, Ponikowski P, Gheorghiade
M, Filippatos G, Krum H, et al. Safety and
tolerability of the novel non-steroidal min-
eralocorticoid receptor antagonist BAY 94-
8862 in patients with chronic heart failure
and mild or moderate chronic kidney disease:
a randomized, double-blind trial. Eur Heart J.
2013 Aug;34(31):2453–63.
43 Minakuchi H, Wakino S, Urai H, Kur-
okochi A, Hasegawa K, Kanda T, et al. The
effect of aldosterone and aldosterone
blockade on the progression of chronic
kidney disease: a randomized placebo-
controlled clinical trial. Sci Rep. 2020
Oct 6;10(1):16626.
44 Ferreira JP, Abreu P, McMurray JJV, van
Veldhuisen DJ, Swedberg K, Pocock SJ, et al.
Renal function stratified dose comparisons of
eplerenone versus placebo in the EMPHA-
SIS-HF trial. Eur J Heart Fail. 2019 Mar;21(3):
345–51.
45 Ando K, Ohtsu H, Uchida S, Kaname S,
Arakawa Y, Fujita T, et al. Anti-albuminuric
effect of the aldosterone blocker eplerenone
in non-diabetic hypertensive patients with
albuminuria: a double-blind, randomised,
placebo-controlled trial. Lancet Diabetes
Endocrinol. 2014 Dec;2(12):944–53.
46 Boesby L, Elung-Jensen T, Strandgaard S,
Kamper AL. Eplerenone attenuates pulse
wave reflection in chronic kidney disease
stage 3-4: a randomized controlled study.
PLoS One. 2013;8(5):e64549.
47 Eschalier R, McMurray JJ, Swedberg K, van
Veldhuisen DJ, Krum H, Pocock SJ, et al.
Safety and efficacy of eplerenone in patients
at high risk for hyperkalemia and/or wors-
ening renal function: analyses of the EM-
PHASIS-HF study subgroups (Eplerenone in
mild patients hospitalization and Survival
Study in Heart Failure). J Am Coll Cardiol.
2013 Oct 22;62(17):1585–93.
48 Tylicki L, Lizakowski S, Rutkowski P, Renke
M, Sulikowska B, Heleniak Z, et al. The en-
hanced renin-angiotensin-aldosteron system
pharmacological blockade: which is the best?
Kidney Blood Press Res. 2012;36(1):335–43.
49 Boesby L, Elung-Jensen T, Klausen TW,
Strandgaard S, Kamper AL. Moderate anti-
proteinuric effect of add-on aldosterone
blockade with eplerenone in non-diabetic
chronic kidney disease. A randomized
cross-over study. PLoS One. 2011;6(11):
e26904.
50 Epstein M, Williams GH, Weinberger M,
Lewin A, Krause S, Mukherjee R, et al. Se-
Am J Nephrol
DOI: 10.1159/000534366
lective aldosterone blockade with eplerenone
reduces albuminuria in patients with type 2
diabetes. Clin J Am Soc Nephrol. 2006 Sep;
1(5):940–51.
51 Tofte N, Lindhardt M, Adamova K, Bakker
SJL, Beige J, Beulens JWJ, et al. Early detec-
tion of diabetic kidney disease by urinary
proteomics and subsequent intervention with
spironolactone to delay progression (PRI-
ORITY): a prospective observational study
and embedded randomised placebo-
controlled trial. Lancet Diabetes Endo-
Downloaded from http://karger.com/ajn/article-pdf/doi/10.1159/000534366/4048477/000534366.pdf by The Library of Nanjing Medical University user on 19 November 2023
crinol. 2020 Apr;8(4):301–12.
52 Beldhuis IE, Myhre PL, Claggett B, Damman
K, Fang JC, Lewis EF, et al. Efficacy and safety
of spironolactone in patients with HFpEF and
chronic kidney disease. JACC Heart Fail.
2019 Jan;7(1):25–32.
53 Chen Y, Liu P, Chen X, Li Y, Zhang F, Wang
Y. Effects of different doses of irbesartan
combined with spironolactone on urinary
albumin excretion rate in elderly patients
with early type 2 diabetic nephropathy. Am
J Med Sci. 2018 May;355(5):418–24.
54 Srivastava A, Adams-Huet B, Vega GL, Toto
RD. Effect of losartan and spironolactone on
triglyceride-rich lipoproteins in diabetic ne-
phropathy. J Investig Med. 2016 Aug;64(6):
1102–8.
55 Kato S, Maruyama S, Makino H, Wada J,
Ogawa D, Uzu T, et al. Anti-albuminuric
effects of spironolactone in patients with
type 2 diabetic nephropathy: a multicenter,
randomized clinical trial. Clin Exp Nephrol.
2015 Dec;19(6):1098–106.
56 Moras N, Caro J, Urrz D, Svano A, Auñón P,
Frnandz C, et al. Diverse diuretics regimens
differentially enhance the antialbuminuric
effect of renin–angiotensin blockers in pa-
tients with chronic kidney disease. Kidney
Int. 2015;88(6):1434–41.
57 Van Buren PN, Adams-Huet B, Nguyen M,
Molina C, Toto RD. Potassium handling with
dual renin-angiotensin system inhibition in
diabetic nephropathy. Clin J Am Soc Neph-
rol. 2014 Feb;9(2):295–301.
58 Esteghamati A, Noshad S, Jarrah S,
Mousavizadeh M, Khoee SH, Nakhjavani M.
Long-term effects of addition of mineralo-
corticoid receptor antagonist to angiotensin
II receptor blocker in patients with diabetic
nephropathy: a randomized clinical trial.
Nephrol Dial Transplant. 2013 Nov;28(11):
2823–33.
59 Wang W, Li L, Zhou Z, Gao J, Sun Y. Effect of
spironolactone combined with angiotensin-
converting enzyme inhibitors and/or angioten-
sin II receptor blockers on chronic glomerular
disease. Exp Ther Med. 2013 Dec;6(6):1527–31.
60 Nielsen SE, Schjoedt KJ, Rossing K, Persson
F, Schalkwijk CG, Stehouwer CD, et al. Levels
of NT-proBNP, markers of low-grade in-
flammation, and endothelial dysfunction
during spironolactone treatment in patients
with diabetic kidney disease. J Renin An-
giotensin Aldosterone Syst. 2013 Jun;14(2):
161–6.
15
61 Ziaee A, Abbas Vaezi A, Oveisi S, Javadi A,
Hashemipour S, Kazemifar AM. Effects of
additive therapy with spironolactone on al-
buminuria in diabetes mellitus: a pilot ran-
domized clinical trial. Caspian J Intern Med.
2013 Spring;4(2):648–53.
62 Nielsen SE, Persson F, Frandsen E, Sugaya T,
Hess G, Zdunek D, et al. Spironolactone di-
minishes urinary albumin excretion in patients
with type 1 diabetes and microalbuminuria: a
randomized placebo-controlled crossover study.
Diabet Med. 2012 Aug;29(8):e184–90.
63 Edwards NC, Steeds RP, Chue CD, Stewart
PM, Ferro CJ, Townend JN. The safety and
tolerability of spironolactone in patients with
mild to moderate chronic kidney disease. Br
J Clin Pharmacol. 2012 Mar;73(3):447–54.
64 Abolghasmi R, Taziki O. Efficacy of low dose
spironolactone in chronic kidney disease with
resistant hypertension. Saudi J Kidney Dis
Transpl. 2011 Jan;22(1):75–8.
65 Zheng H, Qiu H, Liu X. Clinical investigation
of combined therapy with benazepril and
spironolactone in diabetic nephropathy.
Pharma Care Res. 2011;11(4):266–8.
66 Hammer F, Edwards NC, Hughes BA, Steeds
RP, Ferro CJ, Townend JN, et al. The effect of
spironolactone upon corticosteroid hormone
metabolism in patients with early stage
chronic kidney disease. Clin Endocrinol. 2010
Nov;73(5):566–72.
67 Guney I, Selcuk NY, Altintepe L, Atalay H,
Başarali MK, Büyükbaş S. Antifibrotic effects
of aldosterone receptor blocker (spi-
ronolactone) in patients with chronic kidney
disease. Ren Fail. 2009;31(9):779–84.
68 Mehdi UF, Adams-Huet B, Raskin P, Vega
GL, Toto RD. Addition of angiotensin re-
ceptor blockade or mineralocorticoid antag-
onism to maximal angiotensin-converting
enzyme inhibition in diabetic nephropathy.
J Am Soc Nephrol. 2009 Dec;20(12):2641–50.
69 Preston RA, Afshartous D, Garg D, Medrano
S, Alonso AB, Rodriguez R. Mechanisms of
impaired potassium handling with dual
renin-angiotensin-aldosterone blockade in
chronic kidney disease. Hypertension. 2009
May;53(5):754–60.
70 Saklayen MG, Gyebi LK, Tasosa J, Yap J.
Effects of additive therapy with spi-
ronolactone on proteinuria in diabetic pa-
tients already on ACE inhibitor or ARB
therapy: results of a randomized, placebo-
controlled, double-blind, crossover trial.
J Investig Med. 2008 Apr;56(4):714–9.
71 Tylicki L, Rutkowski P, Renke M, Larczyński
W, Aleksandrowicz E, Lysiak-Szydlowska W,
et al. Triple pharmacological blockade of the
renin-angiotensin-aldosterone system in
nondiabetic CKD: an open-label crossover
randomized controlled trial. Am J Kidney
Dis. 2008 Sep;52(3):486–93.
72 van den Meiracker AH, Baggen RG, Pauli S,
Lindemans A, Vulto AG, Poldermans D, et al.
Spironolactone in type 2 diabetic nephrop-
athy: effects on proteinuria, blood pressure
16 Am J Nephrol
DOI: 10.1159/000534366
and renal function. J Hypertens. 2006 Nov;
24(11):2285–92.
73 Bianchi S, Bigazzi R, Campese VM. Long-
term effects of spironolactone on proteinuria
and kidney function in patients with chronic
kidney disease. Kidney Int. 2006 Dec;70(12):
2116–23.
74 Schjoedt KJ, Rossing K, Juhl TR, Boomsma F,
Tarnow L, Rossing P, et al. Beneficial impact
of spironolactone on nephrotic range albu-
minuria in diabetic nephropathy. Kidney Int.
2006 Aug;70(3):536–42.
75 Chrysostomou A, Pedagogos E, MacGregor
L, Becker GJ. Double-Blind, placebo-
controlled study on the effect of the aldo-
sterone receptor antagonist spironolactone in
patients who have persistent proteinuria and
are on long-term angiotensin-converting
enzyme inhibitor therapy, with or without
an angiotensin II receptor blocker. Clin J Am
Soc Nephrol. 2006;1(2):256–62.
76 Schjoedt KJ, Rossing K, Juhl TR, Boomsma
F, Rossing P, Tarnow L, et al. Beneficial
impact of spironolactone in diabetic ne-
phropathy. Kidney Int. the2005;68(6):
2829–36.
77 Rossing K, Schjoedt KJ, Smidt UM, Boomsma
F, Parving HH. Beneficial effects of adding
spironolactone to recommended antihyper-
tensive treatment in diabetic nephropathy: a
randomized, double-masked, cross-over
study. Diabetes Care. 2005 Sep;28(9):
2106–12.
78 Shibata S, Nagase M, Yoshida S, Kawarazaki
W, Kurihara H, Tanaka H, et al. Modification
of mineralocorticoid receptor function by
Rac1 GTPase: implication in proteinuric
kidney disease. Nat Med. 2008 Dec;14(12):
1370–6.
79 Crompton M, Ferguson JK, Ramnath RD,
Onions KL, Ogier AS, Gamez M, et al.
Mineralocorticoid receptor antagonism in
diabetes reduces albuminuria by preserving
the glomerular endothelial glycocalyx. JCI
Insight. 2023 Mar 8;8(5):e154164.
80 Ferreira NS, Bruder-Nascimento T, Pereira
CA, Zanotto CZ, Prado DS, Silva JF, et al.
NLRP3 inflammasome and mineralocorti-
coid receptors are associated with vascular
dysfunction in type 2 diabetes mellitus. Cells.
2019 Dec 8;8(12):1595.
81 Nanba K, Vaidya A, Rainey WE. Aging and
adrenal aldosterone production. Hyperten-
sion. 2018 Feb;71(2):218–23.
82 Roldán J, Morillas P, Castillo J, Andrade H,
Guillén S, Núñez D, et al. Plasma aldosterone
and glomerular filtration in hypertensive
patients with preserved renal function. Rev
Esp Cardiol. 2010 Jan;63(1):103–6.
83 Chen C, Zhu XY, Li D, Lin Q, Zhou K.
Clinical efficacy and safety of spironolactone
in patients with resistant hypertension: a
systematic review and meta-analysis. Medi-
cine. 2020 Aug 21;99(34):e21694.
84 Apperloo AJ, de Zeeuw D, de Jong PE. A
short-term antihypertensive treatment-
induced fall in glomerular filtration rate
predicts long-term stability of renal function.
Kidney Int. 1997 Mar;51(3):793–7.
85 Holtkamp FA, de Zeeuw D, Thomas MC,
Cooper ME, de Graeff PA, Hillege HJ, et al. An
acute fall in estimated glomerular filtration rate
during treatment with losartan predicts a slower
decrease in long-term renal function. Kidney
Int. 2011 Aug;80(3):282–7.
86 Bakris GL, Weir MR. Initial drops in glo-
merular filtration rate with certain drug
classes retard kidney disease progression. Am
Downloaded from http://karger.com/ajn/article-pdf/doi/10.1159/000534366/4048477/000534366.pdf by The Library of Nanjing Medical University user on 19 November 2023
J Nephrol. 2022;53(7):513–5.
87 Fu Y, Hall JE, Lu D, Lin L, Manning RD Jr,
Cheng L, et al. Aldosterone blunts tubulo-
glomerular feedback by activating macula
densa mineralocorticoid receptors. Hyper-
tension. 2012 Mar;59(3):599–606.
88 Barrera-Chimal J, Girerd S, Jaisser F. Min-
eralocorticoid receptor antagonists and kid-
ney diseases: pathophysiological basis. Kid-
ney Int. 2019 Aug;96(2):302–19.
89 Inker LA, Collier W, Greene T, Miao S,
Chaudhari J, Appel GB, et al. A meta-analysis
of GFR slope as a surrogate endpoint for
kidney failure. Nat Med. 2023 Jul;29(7):
1867–76.
90 Yusuf S, Teo KK, Pogue J, Dyal L, Copland I,
Schumacher H, et al. Telmisartan, ramipril,
or both in patients at high risk for vascular
events. N Engl J Med. 2008 Apr 10;358(15):
1547–59.
91 Rutkowski B, Tylicki L. Nephroprotective
action of renin-angiotensin-aldosterone sys-
tem blockade in chronic kidney disease pa-
tients: the landscape after ALTITUDE and
VA NEPHRON-D trails. J Ren Nutr. 2015;
25(2):194–200.
92 Barrera-Chimal J, André-Grégoire G,
Nguyen Dinh Cat A, Lechner SM, Cau J,
Prince S, et al. Benefit of mineralocorticoid
receptor antagonism in AKI: role of vascular
smooth muscle Rac1. J Am Soc Nephrol. 2017
Apr;28(4):1216–26.
93 Barrera-Chimal J, Estrela GR, Lechner SM,
Giraud S, El Moghrabi S, Kaaki S, et al. The
myeloid mineralocorticoid receptor controls
inflammatory and fibrotic responses after
renal injury via macrophage interleukin-4
receptor signaling. Kidney Int. 2018 Jun;
93(6):1344–55.
94 Garthwaite SM, McMahon EG. The evolution
of aldosterone antagonists. Mol Cell Endo-
crinol. 2004 Mar 31;217(1–2):27–31.
95 Agarwal R, Joseph A, Anker SD, Filippatos G,
Rossing P, Ruilope LM, et al. Hyperkalemia
risk with finerenone: results from the FI-
DELIO-DKD trial. J Am Soc Nephrol. 2022
Jan;33(1):225–37.
96 Bramlage P, Swift SL, Thoenes M, Minguet J,
Ferrero C, Schmieder RE. Non-steroidal
mineralocorticoid receptor antagonism for
the treatment of cardiovascular and renal
disease (vol 18, pg 28, 2016). Eur J Heart Fail:
J Working Group Heart Fail Eur Soc Cardiol.
2017(6):19.
Yuan/Gao/Lin/Liu/Shen/Zou/Wang/Shen/
Shao/Liu/Zhang/Pan/Zhu/Yu/Yu/Zhu
97 Epstein M, Kovesdy CP, Clase CM, Sood
MM, Pecoits-Filho R. Aldosterone, min-
eralocorticoid receptor activation, and
CKD: a review of evolving treatment par-
adigms. Am J Kidney Dis. 2022 Nov;80(5):
658–66.
Mineralocorticoid Receptor Antagonists for
Chronic Kidney Disease
98 Lerma E, White WB, Bakris G. Effec- 99 Rossing K, Schjoedt KJ, Smidt UM, Boomsma F,
tiveness of nonsteroidal mineralocorti- Parving HH. Beneficial effects of adding spi-
coid receptor antagonists in patients ronolactone to recommended antihypertensive
with diabetic kidney disease. treatment in diabetic nephropathy: a random-
Postgrad Med. 2022 Apr 20;135(3): ized, double-masked, cross-over study. Diabetes
224–33. Care. 2005 Sep;28(9):2106–12.
Downloaded from http://karger.com/ajn/article-pdf/doi/10.1159/000534366/4048477/000534366.pdf by The Library of Nanjing Medical University user on 19 November 2023
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DOI: 10.1159/000534366