AJN Novel Research Findings

American Journal
of Nephrology Am J Nephrol 2023;54:234–244 Received: March 23, 2023
Accepted: April 24, 2023
DOI: 10.1159/000531000 Published online: May 18, 2023

Discontinuation of Renin-Angiotensin System

Inhibitors and Clinical Outcomes in Chronic
Kidney Disease: A Systemic Review and
Meta-Analysis

Downloaded from http://karger.com/ajn/article-pdf/54/5-6/234/3995108/000531000.pdf by guest on 06 September 2023

Chen Tang a, b, c Xin-Yan Wen d Ji-Cheng Lv a, b, c Su-Fang Shi a, b, c
Xu-Jie Zhou a, b, c Li-Jun Liu a, b, c Hong Zhang a, b, c
aRenal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China; bKey

Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention
and Treatment (Peking University), Ministry of Education, Beijing, China; cResearch Units of Diagnosis and
Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China;
d
Department of Cardiology, Peking University First Hospital, Beijing, China

Keywords and one randomized clinical trial including 244,979 pa-

Meta-analysis · Renin-angiotensin system inhibitors · Chronic tients met the inclusion criteria. Pooled data demonstra-
kidney disease · Mortality · Cardiovascular event · End-stage ted that discontinuation of RAS inhibitors was associated
kidney disease with an increased risk of all-cause mortality (HR 1.42, 95%
CI 1.23–1.63), cardiovascular event risk (HR 1.25, 95% CI
1.17–1.22), and ESKD (HR 1.23, 95% CI 1.02–1.49). In
Abstract sensitivity analyses, the risk for ESKD was reduced. Sub-
Background: Discontinuation of renin-angiotensin sys- group analysis showed that the risk of mortality was
tem (RAS) inhibitors is common in patients with chronic more pronounced in patients with eGFR above 30 mL/
kidney disease (CKD), and the potential danger has been min/m 2 and in patients with hyperkalemia-related dis-
reported in several studies. However, a comprehensive continuation. In contrast, patients with eGFR below
analysis has not been conducted. Objectives: This study 30 mL/min/m 2 were at great risk of cardiovascular
sought to evaluate the effects of discontinuation of RAS events. Conclusions: The discontinuation of RAS inhib-
inhibitors in CKD. Method: Relevant studies up to No- itors in patients with CKD was associated with a signifi-
vember 30, 2022, were identified in the PubMed, Embase, cantly increased risk of all-cause mortality and cardio-
Web of Science, and Cochrane Library databases. Efficacy vascular events. These data suggest that RAS inhibitors
outcomes included the composite of all-cause mortality, should be continued in CKD if the clinical situation
cardiovascular events, and end-stage kidney disease allows. © 2023 The Author(s).
(ESKD). Results were combined using a random-effects Published by S. Karger AG, Basel

or fixed-effects model, and sensitivity analysis used the

leave-one-out method. Results: Six observational studies Chen Tang and Xin-Yan Wen contributed equally to this work.

karger@karger.com © 2023 The Author(s). Correspondence to:

www.karger.com/ajn Published by S. Karger AG, Basel Li-Jun Liu, lijun.liu @ aliyun.com

This article is licensed under the Creative Commons Attribution-

NonCommercial 4.0 International License (CC BY-NC) (http://www.
karger.com/Services/OpenAccessLicense). Usage and distribution for
commercial purposes requires written permission.
 Introduction shown in Supplementary Data 1 (for all online suppl. data, see
https://doi.org/10.1159/000531000). References of all selected ar-
ticles were reviewed to identify any eligible studies. The search was
In patients with chronic kidney disease (CKD), the use restricted to human subjects.
of renin-angiotensin system (RAS) inhibitors, including All RCTs and observational longitudinal studies (prospective or
angiotensin-converting enzyme inhibitors (ACEIs), or retrospective) evaluating the risk of discontinuing RAS inhibitors
angiotensin II receptor blockers (ARBs), is well estab- in adult patients with CKD were eligible for inclusion if the
lished [1, 2]. Adequate RAS inhibitors can retard the incidence of at least one of the following outcomes was reported:
progression of kidney failure to end-stage kidney disease (1) all-cause mortality, (2) cardiovascular events, and (3) ESKD.
We excluded studies with fewer than 100 participants in the initial
(ESKD) by reducing proteinuria and optimizing blood cohort, duplicate studies of the same cohort, and studies including
pressure control [3]. Additionally, prior clinical trials patients under 18 years of age. Studies were required to include a
have shown that RAS inhibitors can slow disease pro- control group with continuation of RAS inhibitors.
gression and reduce the risk of mortality in patients with Two authors (C.T. and X.Y.W.) independently reviewed the
diabetes and cardiovascular diseases (CVDs), such as potential titles, abstracts, and/or full manuscripts to evaluate the
eligibility of studies. Disagreement was resolved by consensus
hypertension, ischemic heart disease, and heart failure involving a third reviewer (L.J.L).
[4–6]. Therefore, RAS inhibitors are recommended by

Downloaded from http://karger.com/ajn/article-pdf/54/5-6/234/3995108/000531000.pdf by guest on 06 September 2023

guidelines for patients with CKD, diabetes, and CVDs [7]. Data Extraction and Study Quality Assessment
However, in routine clinical practice, the use of RASIs in Two reviewers (C.T. and X.Y.W.) extracted data using a stand-
CKD may often be interrupted [8]. Serum creatinine ele- ardized data-extraction form. The details extracted from each
study included the following: author, year of publication, country,
vations, hyperkalemia, and hypotension are all common study design, sample size, demographics and clinical character-
causes for the discontinuation of RAS inhibitors [9]. Re- istics, definition and reason for discontinuation of RAS inhibitors,
cently, there has also been increasing concern about the follow-up duration, and outcomes.
risks of discontinuing RAS inhibitors, and those dangers The Newcastle-Ottawa Scale (NOS) for observational studies [14]
have been reported in relevant studies. In a cohort of and the Cochrane Risk of Bias Tool for RCTs were used to assess the
study quality [15]. Two reviewers independently assessed trial quality
predominantly male veterans with CKD Stages 3 and 4,
(C.T. and X.Y.W.). Any discrepancies about data extraction or quality
ACEI/ARB discontinuation was independently associated score were resolved by referring to a third reviewer (L.J.L.). The details
with an increased risk of subsequent death and ESKD [10]. are available in online supplementary Tables 1 and 2.
In patients with advanced CKD, discontinuation of RAS
inhibitors was associated with an increased risk of cardio- Data Synthesis and Analysis
vascular events and all-cause mortality but not ESKD [11]. The primary outcome was the association between the dis-
continuation of RAS inhibitors and all-cause mortality, cardio-
However, in a newly published randomized controlled trial vascular events, and ESKD. Subgroup analyses were conducted
(RCT), adverse events were similar in the discontinuation according to the eGFR levels and reasons for discontinuation of
and continuation groups [12]. Therefore, we wanted to RAS inhibitors. Precalculated hazard ratios (HRs) with corre-
conduct a systematic review and meta-analysis of published sponding 95% confidence intervals (CIs) were extracted from
studies to better understand the effects of discontinuing the included trials. To control possible confounders, the best-
adjusted estimates were used in the final analysis. The hetero-
RAS inhibitors in patients with CKD. geneity across studies was measured by the I2 statistic. If severe
heterogeneity was present at I2 >50%, random-effect models were
chosen; otherwise, fixed-effect models were used. To evaluate the
Materials and Methods robustness of the pooled results, we performed sensitivity analyses
by excluding studies one by one. Potential publication bias was
This meta-analysis was conducted in accordance with the assessed by funnel plots in combination with both Egger’s test and
Preferred Reporting Items for Systematic Review and Meta- Begg’s test. A two-tailed p value <0.05 was considered statistically
Analyses (PRISMA) statement [13]. Institutional Review Board significant in all analyses. All analyses were performed using R
approval and informed consent were waived as this was not an version 3.4.3 (R Foundation for Statistical Computing, Vienna,
individual patient-level meta-analysis. The protocol was registered Austria; http://www.R-project.org/).
and published in PROSPERO (CRD42022373436).

Literature Search and Inclusion Criteria Results

We searched the PubMed, Embase, Web of Science, and
Cochrane Library databases from the date of inception up to Study Selection and Characteristics
November 30, 2022. Relevant studies were identified using relevant
text words and medical subject headings that included all spellings Our literature search revealed 1,225 nonduplicate ar-
of “CKD,” “chronic renal failure,” “chronic renal insufficiency,” ticles: 1,166 articles were excluded after the title and
and “discontinuation of ACEIs.” The detailed search strategies are abstract were reviewed. After reviewing 59 manuscripts

Discontinuation of RAS Inhibitors in Am J Nephrol 2023;54:234–244 235

Chronic Kidney Disease DOI: 10.1159/000531000
 Downloaded from http://karger.com/ajn/article-pdf/54/5-6/234/3995108/000531000.pdf by guest on 06 September 2023
Fig. 1. Literature flowchart.

for this meta-analysis, we included 7 articles comprising 8 of RAS inhibitors significantly increased the risk by 56%
cohorts that met predefined criteria [10–12, 16–19]. The in patients with eGFR above 30 mL/min/m2 (HR 1.56,
details of the search program in this study are shown in 95% CI 1.30–1.86; p < 0.001; I2 = 95%), but was neutral in
Figure 1. patients with eGFR below 30 mL/min/m2 (HR 1.17, 95%
The characteristics of the participants and studies are CI 0.87–1.58; p = 0.29; I2 = 97%) (Fig. 3). The results were
described in Table 1. Among the 7 retrieved studies, 6 similar when only observational studies were considered
were observational studies, and one [12] was a random- (online suppl. Fig. 2). Regarding the reasons for discon-
ized clinical trial. Four [11, 12, 16, 19] of the studies tinuation, hyperkalemia-related discontinuation of RAS
involved patients with advanced CKD. Three studies inhibitors was also associated with a statistically increased
were from European countries, two were from the USA, risk (HR 1.48, 95% CI 1.29–1.70; p < 0.001; I2 = 85%);
one was from Canada, and the last was from China. The however, patients with eGFR decrease did not experience
definition of discontinuation of RAS inhibitors varied such an increase (HR 1.23, 95% CI 0.90–1.69; p = 0.20;
across the studies, and durations of use ranged from 14 I2 = 98%) (Fig. 3).
to 180 days depending on the prescription. The reported
reasons for discontinuation of RAS inhibitors can be Cardiovascular Events
mainly classified as eGFR decrease [11, 16, 19] and There were five studies in which cardiovascular events
hyperkalemia [17, 18]. were reported, including six cohorts. Discontinuation of
RAS inhibitors significantly increased cardiovascular
All-Cause Mortality event risk (HR 1.25, 95% CI 1.17–1.32; p < 0.001; I2 =
In seven of the studies, including the RCT, all-cause 75%) (Fig. 2b). Sensitivity analysis suggested the same
mortality was reported. The meta-analysis showed that results (online suppl. Table 4). According to the subgroup
discontinuation of RAS inhibitors was associated with an analysis, discontinuation of RAS inhibitors increased the
increased risk of all-cause mortality (HR 1.42, 95% CI risk by 18% in patients with eGFR above 30 mL/min/m2
1.23–1.63; p < 0.001; I2 = 96%) (Fig. 2a). Sensitivity (HR 1.18, 95% CI 1.15–1.21; p < 0.001; I2 = 0%) and by
analyses did not change the result statistically (online 31% in patients with eGFR below 30 mL/min/m2 (HR
suppl. Table 3). In the subgroup analysis, discontinuation 1.31, 95% CI 1.26–1.37; p < 0.001; I2 = 0%). A statistically

236 Am J Nephrol 2023;54:234–244 Tang/Wen/Lv/Shi/Zhou/Liu/Zhang

DOI: 10.1159/000531000
Chronic Kidney Disease
Discontinuation of RAS Inhibitors in
Table 1. Baseline characteristics of enrolled studies

References Country/ Study design Sample Male Age, Baseline Diabetes Definition of Reason of Follow- Outcomes
region size (%) years eGFR mellitus discontinuation discontinuation up
level (mL/ (%) of RAS inhibitors of RAS inhibitors (months)
min/m2)

Qiao et al. [16] America Retrospective 2 410a 41.8% 73.2±13.0 23.7±5.3 48.2 60 days without eGFR decrease 40 Mortality,
(2020) prescriptions cardiovascular
events, ESKD
Walther et al. [10] America Retrospective 141,252 96.7 73.7±10.4 49.3±13.8 42.5 14 days without Uncertain 59 Mortality, ESKD
(2020) prescriptions
Santoro et al. [18] Europe Retrospective 1,762a 57.5 72.4±14.2 – 44.0 Calculating the Hyperkalemia – Mortality,
(2021) proportion of cardiovascular
days covered events
(PDC), <80%
Fu et al. [11] (2021) Europe Retrospective 10,254 64.3 70.0±12.3 22.2±5.9 49.5 60 days without eGFR decrease 60 Mortality,

DOI: 10.1159/000531000
prescriptions cardiovascular
events, ESKD

Am J Nephrol 2023;54:234–244
Leon et al. [17] (2022) Canada Retrospective
Manitoba 7,200 52.5 72.4±13.4 40.9±13.8 63.1 90 days without Hyperkalemia – Mortality,
Cohort prescriptions cardiovascular
events, ESKD
Ontario 71,290 48.3 79.5±7.5 41.2±12.6 58.0 90 days without Hyperkalemia – Mortality,
Cohort prescriptions cardiovascular
events, ESKD
Yang et al. [19] (2022) China Prospective 10,400 46.5 73.3±11.4 29.9±12.4 100.0 180 days eGFR decrease 43 Mortality,
without cardiovascular
prescriptions events, ESKD
Bhandari et al. [12] Europe Randomized 411 68.4 63 17.8±5.2 62.8 – – 36 Mortality, ESKD
(2022) clinical trial
a
Sample size after propensity score matching.

237
Downloaded from http://karger.com/ajn/article-pdf/54/5-6/234/3995108/000531000.pdf by guest on 06 September 2023
 a

Downloaded from http://karger.com/ajn/article-pdf/54/5-6/234/3995108/000531000.pdf by guest on 06 September 2023

b

Fig. 2. Forest plots showing risk estimates of the association between discontinuation of RAS inhibitors and risk of
all-cause mortality, cardiovascular events, and ESKD. a All-cause mortality. b Cardiovascular events. c ESKD.

increased risk of cardiovascular events was also observed that discontinuation of RAS inhibitors did not signifi-
in patients who discontinued RAS inhibitors due to eGFR cantly increase the risk of ESKD (online suppl. Table 5).
decrease and hyperkalemia (Fig. 4). The subgroup analysis showed that patients with eGFR
below 30 mL/min/m2 did not have an increased risk of
End-Stage Kidney Disease ESKD after discontinuation of RAS inhibitors (HR 1.09,
We identified 6 studies in which the effect of with- 95% CI 0.88–1.36; p = 0.43; I2 = 93%), and even when
drawing RAS inhibitors on ESKD was examined. The only observational studies were included, there was no
meta-analysis showed that the risk of ESKD was HR 1.23, significant increased risk (online suppl. Fig. 3). However,
95% CI, 1.02–1.49; p = 0.03; I2 = 98% (Fig. 2c). After the risk of ESKD increased in patients with eGFR above
certain articles were removed, sensitivity analysis showed 30 mL/min/m2 (HR 1.42, 95% CI 1.08–1.88; p = 0.01;

238 Am J Nephrol 2023;54:234–244 Tang/Wen/Lv/Shi/Zhou/Liu/Zhang

DOI: 10.1159/000531000
 Downloaded from http://karger.com/ajn/article-pdf/54/5-6/234/3995108/000531000.pdf by guest on 06 September 2023
a

Fig. 3. a, b The results of subgroup analyses on the association between discontinuation of RAS inhibitors and risk of all-cause mortality.

I2 = 98%). In addition, there was also no statistically and all-cause mortality, cardiovascular events, and ESKD.
increased risk of ESKD in patients who discontinued RAS The funnel plots did not show obvious asymmetry, and
inhibitors due to hyperkalemia (HR 1.35, 95% CI Egger’s regression test and Begg’s test also showed con-
0.91–1.99; p = 0.13; I2 = 98%) and in patients with sistent results (online suppl. Fig. 1).
eGFR decrease (HR 1.10, 95% CI 0.81–1.49; p = 0.53;
I2 = 95%) (Fig. 5).
Discussion
Publication Bias
No publication bias was found in the analysis of the To our knowledge, this is the first systematic review and
association between discontinuation of RAS inhibitors meta-analysis in which the outcomes among patients with

Discontinuation of RAS Inhibitors in Am J Nephrol 2023;54:234–244 239

Chronic Kidney Disease DOI: 10.1159/000531000
 Downloaded from http://karger.com/ajn/article-pdf/54/5-6/234/3995108/000531000.pdf by guest on 06 September 2023
a

Fig. 4. a, b The results of subgroup analyses on the association between discontinuation of RAS inhibitors and risk
of cardiovascular events.

CKD after the discontinuation of RAS inhibitors were [20, 21]. RAS inhibitors can not only delay the progression
evaluated. According to our results, discontinuation of of CKD in patients with albuminuria but also reduce
RAS inhibitors was associated with a significantly increased cardiovascular mortality in postmyocardial infarction pa-
risk of all-cause mortality, cardiovascular events, and ESKD. tients [22]. Data from the HOPE, LIFE, and ALLHAT
Subgroup analysis showed that the risk of mortality was studies confirm the beneficial effects of RAS inhibitors’
more pronounced in patients with eGFR above 30 mL/min/ use for CKD of earlier stages by reducing morbidity,
m2 and in patients with hyperkalemia-related discontinua- mortality, and cardiovascular events [23]. This might ex-
tion. In contrast, patients with eGFR below 30 mL/min/m2 plain why the frequency of adverse clinical outcomes was
were at great risk of cardiovascular events. higher in patients with discontinuation of RAS inhibitors
It is widely recognized that ACEIs/ARBs can be used as with eGFR above 30 mL/min/m2. However, there is equi-
renoprotective drugs in both diabetic and nondiabetic CKD poise regarding the safety and efficacy of RAS inhibitors’ use

240 Am J Nephrol 2023;54:234–244 Tang/Wen/Lv/Shi/Zhou/Liu/Zhang

DOI: 10.1159/000531000
 Downloaded from http://karger.com/ajn/article-pdf/54/5-6/234/3995108/000531000.pdf by guest on 06 September 2023
a

Fig. 5. a, b The results of subgroup analyses on the association between discontinuation of RAS inhibitors and risk of ESKD.

in advanced CKD. RAS inhibitors can also cause hyper- trial, which was the only RCT in which the effects of
kalemia and acute kidney injury, and these risks are espe- stopping RAS inhibitors in patients with advanced CKD
cially high in patients with advanced kidney disease [24, 25]. were evaluated [12]. In this trial, they found similar out-
According to previous observational studies [11, 16] comes in the two groups with respect to ESKD and the
and our meta-analysis results, it appears that discon- incidence of adverse events, although the number of
tinuation of RAS inhibitors has adverse effects in patients with cardiovascular events was higher in the
patients with advanced CKD. From the subgroup anal- discontinuation group than in the continuation group
ysis, we found that discontinuation of RAS inhibitors (108 and 88, respectively) [26]. Statistically, there was
was associated with increased risk of cardiovascular no advantage to continuing with RAS inhibitors. However,
events but a neutral risk of ESKD and mortality in we believe that several factors might obscure the apparent
patients with eGFRs below 30 mL/min/m2. Neverthe- benefits of RAS inhibitors. First, it was a small sample trial
less, this result differed from that of the STOP-ACEi of predominantly European populations. Second, nearly

Discontinuation of RAS Inhibitors in Am J Nephrol 2023;54:234–244 241

Chronic Kidney Disease DOI: 10.1159/000531000
40% of enrolled patients had hereditary or renal vascular zirconium cyclosilicate [34, 35]. These agents can main-
disease with relatively lower proteinuria. However, the tain serum K+ concentrations without imposing limits on
discontinuation group had a relatively higher proportion RAS inhibitors or dietary restrictions [36].
of patients with glomerulonephritis (p = 0.079). Third,
29% of patients had an eGFR under 15 mL/min/1.73 m2, Limitations
and the eGFR decline was relatively slower (decreased by Several limitations of the present meta-analysis
more than 2 mL/min/1.73 m2 per year). In contrast, should be mentioned. Because of the small number
patients in observational trials [11, 16] were newly diag- of studies available, we combined only randomized
nosed with CKD G4, and the eGFR was approximately clinical trials with observational studies in our meta-
20 mL/min/1.73 m2. The rapid decrease in eGFR was also a analysis; since retrospective studies may be biased on
predictive of the need for renal replacement therapy (RRT) the basis of their retrospective design, this is an issue to
and increased mortality [27]. Fourth, there was no in- be considered. The problem of statistical heterogeneity
formation on whether the patients had hyperkalemia could not be solved since most studies were observa-
before enrollment or whether the dosage of RAS inhibitors tional. Second, the precise reasons for stopping RAS
was reduced or withdrawn during the follow-up due to inhibitors remain unknown in some included studies

Downloaded from http://karger.com/ajn/article-pdf/54/5-6/234/3995108/000531000.pdf by guest on 06 September 2023

hyperkalemia. Therefore, for cardiovascular-renal protec- [11, 16, 19], and we can only define it as eGFR decrease
tion, it is possible that the dangers of stopping RAS based on the research design. The definitions of dis-
inhibitors in patients with advanced CKD may be continuation of RAS inhibitors were also not uniform,
underestimated. and this lack of standardization may have resulted in
As a matter of fact, CVD is a leading a cause of death in inaccurate estimates. Furthermore, regarding factors
patients with advanced CKD [28]. The combination of that might affect the results, such as dose changes
RAAS activation, sympathetic overactivity, inflammation, and proteinuria levels, there was no information avail-
and oxidative stress may contribute to the rapid increase in able to analyze their impact. Further studies with larger
cardiovascular events associated with advanced CKD [29, sample sizes are needed to obtain more accurate results.
30]. As a result, patients with advanced CKD are likely to
benefit from continuing RAS inhibitors. Furthermore,
discontinuation of RAS inhibitors theoretically could re- Conclusions
store the capacity for autoregulation within the kidney,
allowing RAAS activation and results in a rise in the GFR In summary, our meta-analysis showed that discon-
[31]. In advanced CKD, even the modest increase in GFR tinuation of RAS inhibitors in patients with CKD was
could delay the onset of RRT. Besides, the majority of these associated with a significantly increased risk of all-cause
patients might die before needing RRT from other causes mortality and cardiovascular events. These data suggest
including CVD. These may explain the lack of significance that if the clinical situation allows, RAS inhibitors should
for the lower eGFR subgroup for ESKD events. be continued in CKD due to the cardioprotective effects.
On the other hand, a significantly increased risk of
mortality, cardiovascular events, and ESKD was found in
patients with hyperkalemia-related discontinuation. In- Statement of Ethics
deed, hyperkalemia is a common and recurring problem
An ethics statement is not applicable because this study is based
for patients prescribed RAS inhibitors’ medications [32]. exclusively on the published literature.
Over 60% of patients with a GFR of 15–45 mL/min/
1.73 m2 discontinue these medications, probably because
of concerns about hyperkalemia and acute kidney injury Conflict of Interest Statement
[8]. However, the optimal approach to treating hyper-
kalemia caused by RAS inhibitors is unclear at present. In The authors have no conflicts of interest to declare.
fact, RAS inhibitors’ discontinuation is the most common
intervention for hyperkalemia, although a number of
other treatments are commonly used [33]. Providers Funding Sources
should carefully consider treating recurrent hyperkalemia
This study was supported by the CAMS Innovation Fund for
before discontinuing RAS inhibitors due to their potential Medical Sciences (2019-I2M-5-046) and The General Program
risks. Novel agents are available to be used as options in (Key Program, Major Research Plan) of National Natural Science
treating hyperkalemia, including patiromer and sodium Foundation of China (82070731).

242 Am J Nephrol 2023;54:234–244 Tang/Wen/Lv/Shi/Zhou/Liu/Zhang

DOI: 10.1159/000531000
 Author Contributions Data Availability Statement

Research idea and study design: L.J.L.; data acquisition: C.T. and All data generated or analyzed during this study are
X.Y.W.; data analysis/interpretation and statistical analysis: C.T. and included in this article and its supplementary materials.
X.Y.W.; and supervision and mentorship: J.C.L., S.F.S., X.J.Z., L.J.L., Further inquiries can be directed to the corresponding
and H.Z. All authors read and approved the final manuscript. author.

References

1 Kidney Disease Outcomes Quality Initiative 11 Fu EL, Evans M, Clase CM, Tomlinson LA, 20 Ruggenenti P, Perna A, Gherardi G, Garini G,
K/DOQI. K/DOQI clinical practice guidelines van Diepen M, Dekker FW, et al. Stopping Zoccali C, Salvadori M, et al. Renoprotective
on hypertension and antihypertensive agents in renin-angiotensin system inhibitors in pa- properties of ACE-inhibition in non-diabetic
chronic kidney disease. Am J Kidney Dis. 2004 tients with advanced CKD and risk of adverse nephropathies with non-nephrotic proteinu-
May;43(5 Suppl 1):S1–290. outcomes: a nationwide study. J Am Soc ria. Lancet. 1999 Jul 31;354(9176):359–64.
2 Wheeler DC, Becker GJ. Summary of KDIGO Nephrol. 2021 Feb;32(2):424–35. 21 Lewis EJ, Hunsicker LG, Clarke WR, Berl T,
guideline. What do we really know about 12 Bhandari S, Mehta S, Khwaja A, Cleland JGF, Pohl MA, Lewis JB, et al. Renoprotective

Downloaded from http://karger.com/ajn/article-pdf/54/5-6/234/3995108/000531000.pdf by guest on 06 September 2023

management of blood pressure in patients Ives N, Brettell E, et al. Renin-angiotensin effect of the angiotensin-receptor antagonist
with chronic kidney disease? Kidney Int. system inhibition in advanced chronic kidney irbesartan in patients with nephropathy due
2013 Mar;83(3):377–83. disease. N Engl J Med. 2022 Nov 3;387(22): to type 2 diabetes. N Engl J Med. 2001 Sep 20;
3 Strippoli GF, Bonifati C, Craig M, Navanee- 2021–32. 345(12):851–60.
than SD, Craig JC. Angiotensin converting 13 Liberati A, Altman DG, Tetzlaff J, Mulrow C, 22 Domanski MJ, Exner DV, Borkowf CB, Geller
enzyme inhibitors and angiotensin II recep- Gotzsche PC, Ioannidis JP, et al. The PRIS- NL, Rosenberg Y, Pfeffer MA. Effect of an-
tor antagonists for preventing the progression MA statement for reporting systematic re- giotensin converting enzyme inhibition on
of diabetic kidney disease. Cochrane Data- views and meta-analyses of studies that eval- sudden cardiac death in patients following
base Syst Rev. 2006 Oct 18(4):CD006257. uate health care interventions: explanation acute myocardial infarction. A meta-analysis
4 Garg R, Yusuf S. Overview of randomized and elaboration. PLos Med. 2009 Jul 21; of randomized clinical trials. J Am Coll Car-
trials of angiotensin-converting enzyme in- 62(10):e1–34. diol. 1999 Mar;33(3):598–604.
hibitors on mortality and morbidity in pa- 14 Stang A. Critical evaluation of the Newcastle- 23 Bhandari S, Ives N, Brettell EA, Valente M,
tients with heart failure. Collaborative Group Ottawa scale for the assessment of the quality Cockwell P, Topham PS, et al. Multicentre
on ACE Inhibitor Trials. JAMA. 1995 May of nonrandomized studies in meta-analyses. randomized controlled trial of angiotensin-
10;273(18):1450–6. Eur J Epidemiol. 2010 Sep;25(9):603–5. converting enzyme inhibitor/angiotensin re-
5 Brenner BM, Cooper ME, de Zeeuw D, Keane 15 Higgins JP, Altman DG, Gotzsche PC, Juni P, ceptor blocker withdrawal in advanced renal
WF, Mitch WE, Parving HH, et al. Effects of Moher D, Oxman AD, et al. The Cochrane disease: the STOP-ACEi trial. Nephrol Dial
losartan on renal and cardiovascular out- Collaboration’s tool for assessing risk of bias Transpl. 2016 Feb;31(2):255–61.
comes in patients with type 2 diabetes and in randomised trials. BMJ. 2011 Oct 18; 24 Ahuja TS, Freeman D Jr., Mahnken JD,
nephropathy. N Engl J Med. 2001 Sep 20; 343(oct18 2):d5928. Agraharkar M, Siddiqui M, Memon A. Pre-
345(12):861–9. 16 Qiao Y, Shin JI, Chen TK, Inker LA, Coresh J, dictors of the development of hyperkalemia
6 Ames MK, Atkins CE, Pitt B. The renin- Alexander GC, et al. Association between in patients using angiotensin-converting en-
angiotensin-aldosterone system and its sup- renin-angiotensin system blockade discon- zyme inhibitors. Am J Nephrol. 2000
pression. J Vet Intern Med. 2019 Mar;33(2): tinuation and all-cause mortality among per- Jul–Aug;20(4):268–72.
363–82. sons with low estimated glomerular filtration 25 Toto RD. RAS blockade, hyperkalemia and
7 Epstein M, Reaven NL, Funk SE, McGaughey rate. JAMA Intern Med. 2020 May 1;180(5): AKI--look and you will find. Nat Rev Neph-
KJ, Oestreicher N, Knispel J. Evaluation of the 718–26. rol. 2012 May;8(5):257–8.
treatment gap between clinical guidelines and 17 Leon SJ, Whitlock R, Rigatto C, Komenda P, 26 Ingelfinger JR. Discontinuation of RAS in-
the utilization of renin-angiotensin-aldosterone Bohm C, Sucha E, et al. Hyperkalemia-related hibitors in advanced CKD - has equipoise
system inhibitors. Am J Manag Care. 2015 Sep; discontinuation of renin-angiotensin-aldosterone occurred? N Engl J Med. 2022 Dec 1;387(22):
21(11 Suppl l):S212–20. system inhibitors and clinical outcomes in 2083–4.
8 Qiao Y, Shin JI, Sang Y, Inker LA, Secora A, Luo CKD: a population-based cohort study. Am 27 Bhatia RT, Browne OT, Naudeer S, Allgar V,
S, et al. Discontinuation of angiotensin convert- J Kidney Dis. 2022 Aug;80(2):164–73.e1. Bhandari S. Examining determinants of pa-
ing enzyme inhibitors and angiotensin receptor 18 Santoro A, Perrone V, Giacomini E, Sangiorgi tient outcome in a low clearance clinic. Neph-
blockers in chronic kidney disease. Mayo Clin D, Alessandrini D, Degli Esposti L. Associa- ron. 2015;129(4):263–8.
Proc. 2019 Nov;94(11):2220–9. tion between hyperkalemia, RAASi non- 28 Collins AJ, Li S, Gilbertson DT, Liu J, Chen
9 Yildirim T, Arici M, Piskinpasa S, Aybal-Kutlu- adherence and outcomes in chronic kidney SC, Herzog CA. Chronic kidney disease and
gun A, Yilmaz R, Altun B, et al. Major barriers disease. J Nephrol. 2022 Mar;35(2):463–72. cardiovascular disease in the Medicare pop-
against renin-angiotensin-aldosterone system 19 Yang A, Shi M, Lau ESH, Wu H, Zhang X, ulation. Kidney Int. 2003 Nov;64(87):S24–31.
blocker use in chronic kidney disease stages Fan B, et al. Clinical outcomes following 29 Ligtenberg G, Blankestijn PJ, Oey PL, Klein
3-5 in clinical practice: a safety concern? Ren discontinuation of renin-angiotensin-system IH, Dijkhorst-Oei LT, Boomsma F, et al.
Fail. 2012;34(9):1095–9. inhibitors in patients with type 2 diabetes and Reduction of sympathetic hyperactivity by
10 Walther CP, Winkelmayer WC, Richardson advanced chronic kidney disease: a prospec- enalapril in patients with chronic renal fail-
PA, Virani SS, Navaneethan SD. Renin- tive cohort study. EClinicalMedicine. 2023 ure. N Engl J Med. 1999 Apr 29;340(17):
angiotensin system blocker discontinuation Jan;55:101751. 1321–8.
and adverse outcomes in chronic kidney
disease. Nephrol Dial Transpl. 2021 Sep 27;
36(10):1893–9.

Discontinuation of RAS Inhibitors in Am J Nephrol 2023;54:234–244 243

Chronic Kidney Disease DOI: 10.1159/000531000
30 Matsushita K, Ballew SH, Wang AY, Kalye- 33 Chang AR, Sang Y, Leddy J, Yahya T, Kirch- 35 Bakris GL, Pitt B, Weir MR, Freeman MW,
subula R, Schaeffner E, Agarwal R. Epidemi- ner HL, Inker LA, et al. Antihypertensive Mayo MR, Garza D, et al. Effect of pa-
ology and risk of cardiovascular disease in medications and the prevalence of hyperka- tiromer on serum potassium level in pa-
populations with chronic kidney disease. Nat lemia in a large health system. Hypertension. tients with hyperkalemia and diabetic kid-
Rev Nephrol. 2022 Nov;18(11):696–707. 2016 Jun;67(6):1181–8. ney disease: the AMETHYST-DN random-
31 Ahmed A, Jorna T, Bhandari S. Should we 34 Kosiborod M, Rasmussen HS, Lavin P, Qu- ized clinical trial. JAMA. 2015 Jul 14;
STOP angiotensin converting enzyme nibi WY, Spinowitz B, Packham D, et al. 314(2):151–61.
inhibitors/angiotensin receptor blockers Effect of sodium zirconium cyclosilicate on 36 Palmer BF. Potassium binders for hyperka-
in advanced kidney disease? Nephron. potassium lowering for 28 days among out- lemia in chronic kidney disease-diet, renin-
2016;133(3):147–58. patients with hyperkalemia: the HARMO- angiotensin-aldosterone system inhibitor
32 Nilsson E, Gasparini A, Arnlov J, Xu H, NIZE randomized clinical trial. JAMA. therapy, and hemodialysis. Mayo Clin Proc.
Henriksson KM, Coresh J, et al. Incidence 2014 Dec 3;312(21):2223–33. 2020 Feb;95(2):339–54.
and determinants of hyperkalemia and hypo-
kalemia in a large healthcare system. Int
J Cardiol. 2017 Oct 15;245:277–84.

Downloaded from http://karger.com/ajn/article-pdf/54/5-6/234/3995108/000531000.pdf by guest on 06 September 2023

244 Am J Nephrol 2023;54:234–244 Tang/Wen/Lv/Shi/Zhou/Liu/Zhang

DOI: 10.1159/000531000