Comparative proteinuria management of

different angiotensin-converting enzyme

inhibitors or angiotensin receptor
blockers for normotensive patients with
CKD: a Bayesian network meta-analysis
Huizhen Ye* , Zhihao Huo* , Peiyi Ye, Guanqing Xiao, Zhe Zhang, Chao Xie and
Yaozhong Kong
Nephrology Department, The First People’s Foshan Hospital, Foshan, Guangdong, China
*
These authors contributed equally to this work.

ABSTRACT
Background. Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin
receptor blockers (ARBs) are blood pressure-lowering agents, but they are also
being used to control proteinuria in early chronic kidney disease (CKD) patients.
However, clinically, some patients present merely proteinuria without hypertension.
No guidelines pointed out how to select treatments for proteinuria in normotensive
patients. Thus, we conducted a Bayesian network analysis to evaluate the relative effects
of different kinds of ACEI or ARB or their combination on proteinuria and blood
pressure reduction.
Methods. The protocol was registered in PROSPERO with ID CRD42017073721.
A comprehensive literature database query was carried out systematically according
to PICOS strategies. The primary outcome was reduction in proteinuria, and the
secondary outcomes were eGFR reduction and blood pressure reduction. Random-
effects pairwise and Bayesian network meta-analyses were used to estimate the effect of
different regimens.
Results. A total of 14 RCTs with 1,098 patients were included in the analysis. All
Submitted 2 September 2019 treatment strategies of ACEI, ARB or their combination had significantly greater efficacy
Accepted 16 January 2020
Published 12 March 2020 in reducing proteinuria than placebo in normotensive CKD patients. The combination
therapy of olmesartan+temocapril had the highest probability (22%) of being the most
Corresponding author
Yaozhong Kong, [email protected] effective treatment to reduce proteinuria in normotensive CKD patients. Olmesartan
and lisinopril ranked second (12%), and temocapril ranked third (15%) but reduced
Academic editor
Stefano Menini blood pressure less than placebo. For IgA nephropathy, the combination therapy
of olmesartan+temocapril also had the highest probability (43%) of being the best
Additional Information and
Declarations can be found on antiproteinuric treatment, while enalapril had the highest probability (58%) of being
page 14 the best antiproteinuric therapy for diabetic nephropathy.
DOI 10.7717/peerj.8575 Conclusions. The combination therapy of olmesartan plus temocapril appeared to be
the most efficacious for reducing proteinuria in normotensive CKD patients and IgA
Copyright nephropathy, but the clinical application should be balanced against potential harms.
2020 Ye et al.
Temocapril can be an option when practitioners are searching for more proteinuria
Distributed under reduction but less blood pressure variation. In normotensive diabetic nephropathy,
Creative Commons CC-BY 4.0 monotherapy with the ACEI enalapril seems to be the most efficacious intervention
OPEN ACCESS

How to cite this article Ye H, Huo Z, Ye P, Xiao G, Zhang Z, Xie C, Kong Y. 2020. Comparative proteinuria management of different
angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for normotensive patients with CKD: a Bayesian network meta-
analysis. PeerJ 8:e8575 http://doi.org/10.7717/peerj.8575
 for reducing albuminuria. Future studies are required to give a more definitive
recommendation.

Subjects Drugs and Devices, Global Health, Internal Medicine, Nephrology, Public Health
Keywords Proteinuria reduction, Normotension, Chronic kidney disease, ACEI, ARB, Bayesian
network analysis.

INTRODUCTION
Chronic kidney disease (CKD) has become a significant public health problem. The
National Center for Chronic Disease Prevention and Health Promotion reported a 15%
overall prevalence of CKD in adults in the United States, suggesting there are approximately
37 million people with CKD in 2019 (National Center for Chronic Disease Prevention and
Health Promotion, 2019). Proteinuria is one of the most common signs for early CKD
patients. Promoting inflammation and fibrosis of kidneys, proteinuria has been perceived
as a strong marker of kidney damage, which is closely related to a high risk of CKD
progression (Avasare & Radhakrishnan, 2015; Chen, Wada & Chiang, 2017). Angiotensin
receptor-blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) are two
kinds of blood pressure-lowering agents that are also used to control proteinuria in early
CKD patients on the basis of clinical practice guidelines.
Indeed, some patients present merely proteinuria without hypertension clinically,
especially among the early CKD patients. A previous meta-analysis (Geng et al., 2014)
suggested that compared with the placebo group, the ARB group had a significant reduction
in urinary protein excretion and better renoprotective effects in normotensive patients
with CKD, but it did decrease both diastolic and systolic blood pressure. The reduction
in blood pressure in normotensive patients may sometimes result in hypotension. What
should be recommended for more proteinuria reduction and less blood pressure reduction
in normotensive patients with CKD? A recent network meta-analysis by Huang et al. (2017)
reported that the ACEI-ARB combination therapy of trandolapril+candesartan was the
most efficacious in reducing albuminuria for normotensive diabetic patients. The study
only included the diabetic patients, which means that the results cannot be generalized to
normotensive patients with other kinds of CKD. It also did not report the effects on blood
pressure reduction, which is important for clinical practitioners.
The objective of this article is to evaluate the relative effects of different kinds of ACEI
or ARB or their combination on proteinuria reduction, including which therapy would be
more suitable for normotensive patients with proteinuria but who need less blood pressure
fluctuation.
Bayesian network analysis is an extension of traditional meta-analysis, which can make
indirect comparisons of two treatments through a common comparator in the absence of
head-to-head direct randomized controlled trials (Herrera-Gomez et al., 2019). Therefore,
we performed a Bayesian network analysis to evaluate the relative proteinuria reduction and
blood pressure changes by various ACEIs or ARBs or their combination for normotensive
patients with CKD.

Ye et al. (2020), PeerJ, DOI 10.7717/peerj.8575 2/17

 METHODS
Study design
Our network meta-analysis was conducted by the rules of Preferred reporting items
for systematic review and meta-analysis protocols (PRISMA-P) 2015 (Shamseer et al.,
2015) and the PRISMA Extension Statement for Reporting of Systematic Reviews
Incorporating Network Meta-analyses of Health Care Interventions (Hutton et al.,
2015). This study was performed using the Bayesian network analysis model, which
is based on generalized linear models . The protocol of this study was registered in
https://www.crd.york.ac.uk/prospero/, an international register of systematic reviews,
which can be available with ID CRD42017073721.

Search strategy
We searched PubMed, the Cochrane Liberary, Embase, CBMdisc, Wanfang database,
and CNKI with the PICOS strategy with advanced searches and Mesh searches with a
cut-off date of June 2019 without language restrictions. We also searched the System
for Information on Grey literature (SIGLE), master’s and doctoral dissertations, and
meeting records in the Chinese database CNKI for grey literature. The text words
for searching included ‘‘normotensive, proteinuria, albuminuria, microalbuminuria,
angiotensinreceptor-blockers, ARB, angiotensin-converting enzyme inhibitor, ACEI, the
names of currently available ARBs or ACEI (losartan, valsartan, irbesartan,candesartan,
telmisartan, eprosartan, olmesartan, imidapril, enalapril, lisinopril, captopril, cilazapril,
ramipril, perindopril, and fosinopril)’’. Meanwhile, we also checked the reference lists of
review articles, meta-analysis, and original studies in order to cover more eligible trials.
The PICOS for our review was as follows:
Intervention: angiotensin-receptor-blockers, ARB, angiotensin-converting enzyme
inhibitor, ACEI, the names of currently available ARBs or ACEIs (losartan, valsartan,
irbesartan, candesartan, telmisartan, eprosartan, olmesartan, imidapril, enalapril, lisinopril,
captopril, cilazapril, ramipril, perindopril, and fosinopril).
Comparator: angiotensin-receptor-blockers, ARB, angiotensin-converting enzyme
inhibitor, ACEI, placebo, other antihypertensive agents
Outcomes
Primary outcomes: urinary protein excretion: proteinuria, urinary albumin excretion
Secondary outcomes:
Glomerular filtration rate (GFR).
Blood pressure (BP), systolic blood pressure (SBP)
Study design: randomized controlled trials (RCTs)

Inclusion and exclusion criteria

Studies meeting the following inclusive criterion were eligible: (1) randomized controlled
trials (RCTs); (2) participants aged 18 years or older; (3) with kidney disease and reporting
proteinuria; (4) specifically analyzing and stating normotension of all the participants.
Patients with dialysis or kidney transplantation were excluded.

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 Data extraction and quality assessment
Data was extracted from all primary studies by two independent researchers (Huizhen Ye
and Zhihao Huo) according to the registered protocol, including article information about
CASP Checklist (Critical Appraisal Skills Programme, 2018) for quality assessment, first
author’s name, publication year, geographic region and participant characteristics (sample
size, mean age, gender, duration of intervention). We resolved disagreements through
discussion with a third researcher to reach consensus (Yaozhong Kong).
In addition, we used the five-point Jadad Score to assess the methodological quality of
studies, which mainly evaluated three aspects (randomisation, blinding, withdrawals and
dropouts) of all the studies. Score ≤2 points was defined as low quality, while score ≥3
points was ranked as high quality. We also used the CASP Checklist, an 11-question list,
to help us make sense of the RCTs we included and complete the quality assessment. It is
made up three sections concentrating on three problems: (A) Are the results of the study
valid? (B) What are the results? (C) Will the results help locally? Only for studies with more
than two ‘‘Y’’ answers in section (A) is worth proceeding with the remaining questions.

Data analysis
The primary outcome in this study was proteinuria reduction. The secondary outcomes
were the reduction in blood pressure and GFR. A standard pairwise meta-analysis of the
same interventions was performed using ADDIS 1.16.5 software (Aggregate Data Drug
Information System, The Netherlands) with a random-effects model. Heterogeneity was
assessed with the I2 metric, and Bayesian network analysis was conducted using ADDIS
1.16.5 software in a Bayesian Markov chain Monte Carlo framework with a consistency
model or an inconsistency model. For the ranking of the interventions, stochastic multi-
criteria acceptability analysis (SMAA)-based models were used (Van Valkenhoef et al.,
2013). For antiproteinuric analysis, 4 chains including 20,000 burn-ins, 50,000 simulation
iterations, 10,000 inference samples and a thinning interval of 10 for each chain were
applied. Convergence was assessed by comparing within-chain and between-chain variance
to calculate the potential scale reduction factor (PSRF) (Jing et al., 2012).The PSRF was
extremely close to 1.00, showing good convergences of iterations.
The Consistency and inconsistency of the RCTs included in the network was also
assessed by the Higgins model with Stata MP 14 (64-bit) (Computer Resource Center,
USA), inconsistency factor and node-splitting analysis with ADDIS 1.16.5 software, to
explore whether the direct and indirect evidence were in agreement. Conclusions could be
drawn by a consistency model if no relevant inconsistency existed.
A basic network diagram was drawn with Stata MP 14 (64-bit) to show the connections
between all the included treatments.

RESULTS
Literature selection and study characteristics. A total of 1,538 records were identified from
our initial literature query. After title and abstract screening, a total of 75 records remained
and were assessed for full texts screening. Since 10 full texts could not be obtained, 65
articles were read through, and articles were excluded for various reasons listed in the

Ye et al. (2020), PeerJ, DOI 10.7717/peerj.8575 4/17

 Figure 1 Flow diagram.
Full-size DOI: 10.7717/peerj.8575/fig-1

flowchart (Fig. 1). Finally, 16 RCT studies met the inclusion and exclusion criteria, but 2
studies were excluded after quality assessment for low Jaded score (1 point), so 14 RCTs
with 1098 patients were included in the meta-analysis. The flowchart summarizing the
study selection process is provided in Fig. 1. A summary of the characteristics of the
included studies is shown in Table 1 and CASP checklist of included studies presented in
Table 2.
Results of meta-analysis. Figure 2 shows the meta-analysis results for proteinuria, blood
pressure and GFR reduction among the normotensive CKD patients, revealing that: (1)
all the treatment strategies had a significantly better effect on reducing proteinuria than
placebo; (2) the combination therapy of candesartan and trandolapril and the ACEI
trandolapril alone were better than candesartan alone, with SMD = 2.87 (95% CI [1.86–
3.87]) and SMD = 1.91 (95% CI [1.06–2.76]), respectively; (3) trandolapril alone, with
SMD = −0.93 (95% CI [−1.67 to −0.2]), was not better than combination treatment with

Ye et al. (2020), PeerJ, DOI 10.7717/peerj.8575 5/17

Ye et al. (2020), PeerJ, DOI 10.7717/peerj.8575

Table 1 Characteristics of included RCTs.

Reference Country Jadad Number for Interventions Age Sex N Follow-up Nephropathy
of origin scores interventions (Male/ (months)
Female)
Horita et al. (2004) Japan 2 3 G1:temocapril G1:39.6 ± 10.8 G1:4/6 G2: 31 6 IgA Nephropathy
1 mg qd G2:42.7 ± 12.0 5/5 G3:5/6
G2:losartan G3:39.6 ± 10.4
12.5 mg qd
G3: temocapril 1
mg+losartan 12.5 mg
qd
Maschio et al. (1994) Italy 4 2 G1:fosinopril NS NS 78 8 IgA Nephropathy
20 mg qd
G2: placebo
Nakamura et al. (2007) Japan 3 3 G1:olmesartan G1:34 ± 7 G1:5/3 24 3 IgA Nephropathy
10 mg qd G2:31 ± 8 G2:4/4
G2:temocapril G3:31 ± 7 G3:4/4
2 mg qd
G3:olmesartan 10
mg+ temocapril 2 mg
qd
Odabas et al. (2001) Turkey 2 2 G1:losartan 50 mg qd G1:34.3 ± 5.9 G1:14/8 44 24 Secondary Amyloidosis
G2:placebo G2:32.2 ± 4.3 G2:14/8
Ravid et al. (1993) Israel 5 2 G1:enalapril 10 mg G1:43.5 ± 3 G1:21/28 94 60 Diabetic Nephropathy
qd G2:placebo G2:44.8 ± 3.5
G2:21/24
Renke et al. (2004) Poland 2 3 G1:losartan 25 mg qd G1:40.4 ± 11.9 G1:7/11 52 9 IgA Nephropathy
G2: enalapril G2:43.4 ± 10.1 G2:12/6
10 mg qd G3:37.7 ± 12.7 G3:11/5
G3::losartan 25
mg+enalapril 10 mg
qd
Shen et al. (2012) China 3 2 G1:losartan 50 mg qd G1:50.2 ± 10.4 G1:58/54 226 12 Nondiabetic Chronic
G2:placebo G2:49.1 ± 11.5 G2:56/58 Kidney Disease
Shimizu et al. (2008) Japan 3 2 G1:losartan G1:36.0 ± 8.5 G1:11/7 36 12 IgA Nephropathy
12.5 mg qd G2:35.7 ± 8.1 G2:6/12
G2:placebo
Kosmadakis et al. (2010) Greece 2 2 G1:lisinopril G1:52.1 ± 15.3 G1:6/7 27 12 idiopathic membranous
10 mg qd G2:50.5 ± 15.5 G2:7/7 nephropathy
G2:losartan 100
mg qd
Acbay (2001) Turkey 2 2 G1:enalapril 5 mg qd Total:29.4 ± 5.2 NS 16 2 Diabetic Nephropathy
G2:losartan 25 mg qd
6/17

(continued on next page)

Ye et al. (2020), PeerJ, DOI 10.7717/peerj.8575

Table 1 (continued)
Reference Country Jadad Number for Interventions Age Sex N Follow-up Nephropathy
of origin scores interventions (Male/ (months)
Female)
Usta et al. (2003) Turkey 3 2 G1:losartan 50 mg qd G1:32 ± 10 G1:8/5 23 12 Focal Segmental
G2:placebo G2:32 ± 13 G2:6/4 Glomerular Sclerosis
Agha et al. (2009) Pakistan 3 2 G1:losartan 50 mg qd G1:53.9 ± 11.1 NS 361 6 Diabetic Nephropathy
G2:placebo G2:54.7 ± 10.9
Atmaca & Gedik (2006) Turkey 2 3 G1: lisinopril G1:55.1 ± 8.9 G1:4/5 26 12 Diabetic Nephropathy
10 mg qd G2:55.1 ± 9.2 G2:4/5
G2:losartan 50 mg qd G3:55.1 ± 9.6 G3:3/5
G3:lisinopril 10
mg+losartan 50 mg
qd
Nakamura et al. (2002) Japan 3 4 G1:trandolapril G1:57.0 ± 9.5 G:10/5 60 18 Diabetic Nephropathy
2 mg qd G2:56.5 ± 10.0 G2:11/4
G2:candesartan G3:57.8 ± 9.0 G3:10/5
8 mg qd G4:54.8 ± 9.3
G3:trandolapril 2
mg+candesartan 8
mg qd
Notes.
NS, not state; G1, Group 1; G2, Group 2; G3, Group 3; G4, Group 4.
Values are mean [SD].
7/17
Ye et al. (2020), PeerJ, DOI 10.7717/peerj.8575

Table 2 CASP checklist of included RCTs.

Reference Section A Section B Section C

Q1 Q2 Q3 Q4 Q5 Q6 Q7 (1. What outcomes were measured ?) (2.Is the primary Q8: confidence Q9 Q10 Q11
outcome clearly limits metioned?
specified ?)

Horita et al. (2004) Y Y Y Y Y Y proteinuria, SBP, DBP, MAP, serum creatinine, serum total protein Y NS Y Y Y

Maschio et al. (1994) Y Y Y Y NS Y proteinuria, eGFR, MAP Y NS Y Y Y

Maschio et al. (1994) Y Y Y N Y Y proteinuria, eGFR, serum creatinine, L-FABP,8-OHdG Y NS Y Y Y

Odabas et al. (2001) Y NS Y NS Y Y proteinuria, serum creatinine Y NS Y Y Y

Ravid et al. (1993) Y Y Y Y Y Y Serum creatinine, Proteinuria, MBP Y Y Y Y Y

Renke et al. (2004) Y Y Y N Y Y proteinuria, SBP, DBP, serum creatinine Y NS Y Y Y

Shen et al. (2012) Y Y Y N Y Y proteinuria, eGFR, SBP, DBP, serum creatinine, serum uric acid Y NS Y Y Y

Shimizu et al. (2008) Y Y Y N Y Y proteinuria, serum uric acid, eGFR and so on Y NS Y Y Y

Kosmadakis et al. (2010) Y Y Y NS Y Y proteinuria, GFR, MAP and so on Y NS Y Y Y

Acbay (2001) Y Y Y Y Y Y SBP, DBP, UAER Y Y Y Y Y

Usta et al. (2003) Y Y Y Y Y Y MAP, proteinuria, creatinine and so on Y NS Y Y Y

Agha et al. (2009) Y Y Y Y Y Y SBP, DBP, serum creatinine, 24-hour urinary microalbumin Y NS Y Y Y

Atmaca & Gedik (2006) Y Y Y Y Y Y 24-hour UAER Y NS Y Y Y

Nakamura et al. (2002) Y Y Y NS Y Y UAE, BP Y Y Y Y Y

Notes.
UAER, urinary albumin excretion; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure;; L-FABP, Liver-type fatty acid-binding protein.
Q1: Did the trial address a clearly focused issue? Q2: Was the assignment of patients to treatments randomised? Q3: Were all of the patients who entered the trial properly accounted for at its conclusion?
Q4: Were patients, health workers and study personnel ‘blind’ to treatment? Q5: Were the groups similar at the start of the trial? Q6: Aside from the experimental intervention, were the groups treated
equally? Q7: How large was the treatment effect? Q8: How precise was the estimate of the treatment effect? Q9: Can the results be applied to the local population, or in your context? Q10: Were all clini-
cally important outcomes considered? Q11: Are the benefits worth the harms and costs?
8/17
 Figure 2 Response rates for efficacy in meta-analyses of direct comparisons between each pair of drugs.
Full-size DOI: 10.7717/peerj.8575/fig-2

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 Figure 3 Network plot.
Full-size DOI: 10.7717/peerj.8575/fig-3

candesartan plus trandolapril ; (4) combination therapy with olmesartan and temocapril,
with SMD = 1.55 (95% CI [0.48–2.63]), was better than monotherapy of olmesartan.
Results of Bayesian network analysis.
First, proteinuria reduction was reported in all 14 trials(Acbay, 2001; Agha et al., 2009;
Atmaca & Gedik, 2006; Horita et al., 2004; Kosmadakis et al., 2010; Maschio et al., 1994;
Nakamura et al., 2007; Nakamura et al., 2002; Odabas et al., 2001; Ravid et al., 1993; Renke
et al., 2004; Shen et al., 2012; Shimizu et al., 2008; Usta et al., 2003). The network map of
eligible comparisons for proteinuria reduction is presented in Fig. 3, showing the direct
comparisons for our network analysis. The consistency was tested in three aspects: (1)
The Higgins model calculated with Statas showed no evidence for inconsistency, with
P = 0.877 (P > 0.05). (2) The inconsistency factor was −0.18 (95% CI [−8.84–6.86]).
This 95% CI contained the neutral value (zero), suggesting the data was consistent. (3)
Node-splitting analysis of proteinuria reduction, shown in Table 3, suggested the direct
and indirect evidence on the split nodes were in agreement, with all the P > 0.05. Hence,
we conducted the Bayesian network analysis with consistency random effect models
(Table 4). Based on the Bayesian probability framework, the combination therapy of
olmesartan+temocapril had the highest probability (22%) of being the most effective
treatment to reduce proteinuria in normotensive CKD patients, followed by olmesartan

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 Table 3 Node-splitting analysis of proteinuria reduction.

Interventions Direct effect Indirect effect Overall P-Value

Placebo vs. enalapril 0.20 (−4.17, 4.58) 1.62 (−2.15, 5.46) 0.99 (−1.51, 3.70) 0.56
Placebo vs. losartan 1.43 (−0.55, 3.46) 0.04 (−5.67, 5.57) 1.27 (−0.40, 2.97) 0.57
enalapril vs. losartan −0.17 (−3.41, 2.96) 1.24 (−3.57, 6.01) 0.29 (−2.24, 2.66) 0.55
Values are mean [SD]

Table 4 Outcomes of ranking from all RCTs.

Proteinuria reduction BP reduction eGFR reduction

Placebo 10(16%) 7 (14%) 2(24%)
candesartan 13(14%) / /
candesartan+trandolapril / 1 (37%) /
enalapril 9(12%) 3 (20%) 7(86%)
fosinopril 14 (16%) / 5(22%)
lisinopril 2(12%) / 6(48%)
lisinopril+losartan / / /
losartan 5(14%) 6(22%) 4(32%)
losartan+ enalapril / 2(32%) /
olmesartan 2(12%) 5(13%) /
olmesartan + temocapril 1(22%) / /
temocapril 3(15%) 8(17%) 2 (24%)
temocapril+losartan / 3 (14%) 1(35%)
trandolapril / 11(51%) /
Notes.
For Proteinuria reduction, rank 1 is best, rank N is worst.
For eGFR reduction, rank N is best, rank 1 is worst.
For BP reduction, rank N is best, rank 1 is worst.
Values are ranking number (probability).

(12%) and lisinopril (12%), with temocapril ranking third (15%) and placebo in tenth
place.
Second, systolic blood pressure reduction was reported in 8 trials (Acbay, 2001; Agha
et al., 2009; Atmaca & Gedik, 2006; Horita et al., 2004; Nakamura et al., 2002; Renke et al.,
2004; Shen et al., 2012; Shimizu et al., 2008). As the rank was defined as a lesser blood
pressure reduction being better, rank N reduces the blood pressure the least in the
normotensive CKD patients. Via consistency random-effect models, trandolapril ranked
in last place, while placebo ranked the seventh (14%), so trandolapril achieved less blood
pressure reduction function than placebo.
Third, a total of 6 studies were included for network analysis of GFR reduction (Acbay,
2001; Horita et al., 2004; Kosmadakis et al., 2010; Shen et al., 2012; Shimizu et al., 2008; Usta
et al., 2003). Rank N reduced GFR the least, suggesting the best renoprotective effect.
The combination of temocapril plus losartan ranked first (35%), revealing that GFR was
decreased the most, followed by placebo (24%).
Sensitivity analysis. We also performed sensitivity analysis that included IgA nephropathy
and diabetic nephropathy respectively. For IgA nephropathy, olmesartan+temocapril had

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 the highest probability (43%) of being the most effective treatment to reduce proteinuria
in normotensive patients, followed by losartan+ enalapril (24%), temocapril ranking
third (21%) and placebo in eighth place (21%). However, losartan+enalapril appeared
to reduce the most blood pressure (44%), while placebo ranked eighth (39%). Regarding
GFR reduction, temocapril+losartan still ranked first (43%), while placebo ranked fourth
(39%).
For diabetic nephropathy, enalapril had the highest probability (58%) of being the most
effective treatment to reduce proteinuria, followed by candesartan+trandolapril (40%),
trandolapril ranking third (33%) and placebo in eighth place (45%).

DISCUSSION
Our Bayesian network analysis with 14 RCT studies and 1098 patients compared the
relative effects of different kinds of ACEIs or ARBs or their combination in proteinuria
reduction, blood pressure fluctuation and GFR reduction, seeking the best choice for
normotensive patients with proteinuria. In our analysis, all the treatment strategies had
a significantly better effect in reducing proteinuria than placebo in normotensive CKD
patients. Our analysis also revealed that the combination therapy of olmesartan plus
temocapril appeared to be most efficacious in reducing proteinuria in normotensive CKD
patients. Temocapril reduced proteinuria significantly and led to less BP reduction than
placebo, which seems to be a good option for patients with proteinuria and normotension.
For normotensive IgA nephropathy, olmesartan+temocapril combination therapy seems to
be the most efficacious therapy to reduce proteinuria. However, for diabetic nephropathy,
the ACEI monotherapy of enalapril had the highest probability of being the best one to
reduce proteinuria.
The results of the pairwise meta-analysis from this study were consistent with findings
from previous meta-analyses. A 2012 meta-analysis comparing ACEI therapy with
placebo showed a significant reduction in macroalbuminuria in diabetic patients without
hypertension and a trend towards a benefit from the combination therapy of ACEI and
ARB (Lv et al., 2012). Another, 2014 meta-analysis noted that ARBs have beneficial effects
on reducing proteinuria in normotensive patients with renal disease(Geng et al., 2014).
Our study also showed that all the treatments with ACEI, ARB or both lessened proteinuria
significantly more than placebo in normotensive CKD patients, not merely in diabetic
nephropathy patients.
Our analysis showed that the combination therapy of olmesartan plus temocapril
appeared to be the most efficacious treatment for reducing proteinuria in normotensive
CKD patients and IgA nephropathy patients. A previous meta-analysis (Cheng et al., 2012)
also revealed that the combination of ACEI and ARB had a better antiproteinuric effect
than monotherapy with ACEI or ARB. This result may be related to a larger glomerular
capillary pressure reduction, more glomerular permselectivity improvement (Remuzzi et
al., 1999; Woo et al., 2000) and inhibition of the secretion of some transforming growth
factors, such as TGF-β1 (Scaglione et al., 2005; Song et al., 2003), when using combination
therapy compared with monotherapy. A 2015 network meta-analysis (Palmer et al., 2015)
investigated the side effects of the combination therapy of ACEI plus ARB. It showed a

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 tendency towards acute kidney injury, stroke, hyperkalaemia, presyncope, and cough when
compared to placebo, though the results were not significant. Fried’s study (Fried et al.,
2013) in 2013 also mentioned that combination therapy increased the risk of hyperkalaemia
and acute kidney injury. The 2012 KDIGO Clinical Practice Guideline for the Evaluation
and Management of CKD (Inker et al., 2014) also did not recommend for combination
therapy of ACEI plus ARB therapy for the obvious side effects mentioned above. Thus,
the clinical application of combined ACEI and ARB should be balanced against the
potential harm. Notably, Homma et al. (2004) reported that the proteinuria-reducing
effect of combination therapy with ARB plus ACEI was independent of the effects on blood
pressure. Thus, if we are searching for therapy with more proteinuria reduction and less
blood pressure reduction, emocapril would be an option, as it ranked third in decreasing
proteinuria and resulted in less blood pressure reduction than the placebo.
A previous network meta-analysis (Huang et al., 2017) found that the combination
therapy of trandolapril plus candesartan was the best one to reduce albuminuria in
normotensive diabetic patients. However, Mann et al. (2008) also mentioned that the
combination therapy of ACEI and ARB reduced proteinuria to a greater extent but had
less renal benefit in diabetic patients. Because of the increased harm of combination
usage, the 2014 (Kidney Disease Outcomes Quality Initiative) KDOQI US commentary
(Inker et al., 2014) advocated monotherapy with either ACEI or AEB. In our analysis, the
monotherapy of enalapril had the highest probability of being the most effective treatment
to reduce proteinuria, while the combination of trandolapril plus candesartan ranked
second for normotensive diabetic patients. The difference may account for the various
included criteria. However, for clinical practitioners, enalapril alone could be an option
for normotensive diabetic patients.
There are several limitations to our analysis. First, we screened the records focusing on
the primary outcome of proteinuria first, so that some of the studies reported no secondary
endpoints. Second, measurements of proteinuria were not totally consistent across all
included studies. For example, some studies reported albumin excretion rate (µg/min)
but not 24-hour urinary protein excretion (g/d). Third, the conclusion cannot be applied
to severe renal impairment or dialysis patients because most of the row data were from
mild or no renal impairment patients. Finally, treatment dosing was not fixed during our
analysis and some studies were even allowed drug dose titration.

CONCLUSIONS
In summary, the combination therapy of olmesartan plus temocapril appears to have a
stronger antiproteinuric effect for normotensive CKD patients and IgA nephropathy, but
the clinical application should be balance against the potential harms. Temocapril might
be an option when practitioners need to reduce proteinuria more but blood pressure less.
For diabetic nephropathy, the ACEI monotherapy of enalapril had the highest probability
of reducing albuminuria for normotensive diabetic patients. However, future studies are
required to make a more definitive recommendation.

Ye et al. (2020), PeerJ, DOI 10.7717/peerj.8575 13/17

 ADDITIONAL INFORMATION AND DECLARATIONS

Funding
The authors received no funding for this work.

Competing Interests
The authors declare there are no competing interests.

Author Contributions
• Huizhen Ye and Zhihao Huo conceived and designed the experiments, performed the
experiments, analyzed the data, prepared figures and/or tables, authored or reviewed
drafts of the paper, and approved the final draft.
• Peiyi Ye, Chao Xie and Yaozhong Kong analyzed the data, authored or reviewed drafts
of the paper, and approved the final draft.
• Guanqing Xiao performed the experiments, authored or reviewed drafts of the paper,
and approved the final draft.
• Zhe Zhang conceived and designed the experiments, authored or reviewed drafts of the
paper, and approved the final draft.

Data Availability
The following information was supplied regarding data availability:
The raw measurements are available in the Supplementary Files.

Supplemental Information
Supplemental information for this article can be found online at http://dx.doi.org/10.7717/
peerj.8575#supplemental-information.

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