Perspective

Use of Renin-Angiotensin System Blockade in Advanced

CKD: An NKF-KDOQI Controversies Report
Matthew R. Weir, Jay I. Lakkis, Bernard Jaar, Michael V. Rocco, Michael J. Choi, Holly Mattrix-Kramer, and
Elaine Ku

Multiple clinical trials have demonstrated that renin-angiotensin system (RAS) blockade with either Complete author and article
angiotensin-converting enzyme inhibitors or angiotensin receptor blockers effectively reduces chronic information provided before
references.
kidney disease (CKD) progression. However, most clinical trials excluded participants with advanced
CKD (ie, estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2). It is acknowledged Am J Kidney Dis. XX(XX):
that initiation of RAS blockade is often associated with an acute reduction in eGFR, which is thought 1-12. Published online
Month X, 2018.
to be functional, but may result in long-term preservation of kidney function through the reductions
in glomerular intracapillary pressure conferred by these agents. In this National Kidney doi: 10.1053/
Foundation–Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) report, we discuss the con- j.ajkd.2018.06.010
troversies regarding use of RAS blockade in patients with advanced kidney disease. We review © 2018 by the National
available published data on this topic and provide perspective on the impact of RAS blockade on Kidney Foundation, Inc.
changes in eGFRs and potassium levels. We conclude that more research is needed to evaluate the
therapeutic index of RAS blockade in patients with advanced CKD.

Introduction remaining kidney function or even accelerate eGFR

The 2012 KDIGO (Kidney Disease: Improving Global Out-
comes) clinical practice guideline for the evaluation and
management of chronic kidney disease (CKD),1 as well as
the KDIGO clinical practice guideline for the management of
blood pressure (BP),2 have both recommended that renin-
angiotensin system (RAS)-blocking drugs, namely
angiotensin-converting enzyme (ACE) inhibitors or angio-
tensin II receptor blockers (ARBs), be used in adults with
and without diabetes mellitus and urine protein excretion >
300 mg/d, especially if BP is elevated. Both guidelines also
suggest that ACE inhibitors or ARBs should be preferred
therapies in patients with non–dialysis-dependent (NDD)
diabetic CKD and urine albumin excretion between 30 and
300 mg/d, even in the absence of high BP.
Currently, there are no statements in either KDIGO
guideline that provide guidance regarding estimated
glomerular filtration rate (eGFR) thresholds for which these
recommendations would not be indicated. The only
reference to the cessation of ACE inhibitor or ARB therapy
in the KDIGO CKD management guideline is in the
setting of intercurrent illnesses in individuals with
eGFRs < 60 mL/min/1.73 m2 who may be at increased
risk for acute kidney injury (AKI).1 In contrast, the KDIGO
guideline on BP management approached this controversy
by suggesting that the current evidence from clinical studies
does not support the discontinuation of ACE inhibitor or
ARB therapy in patients with advanced NDD-CKD for the
purpose of trying to maintain kidney function, although
hyperkalemia or hypotension may be specific reasons for
discontinuing use of these agents in some patients.2
More recently, the value of commencing or continuing
BP-lowering regimens based on RAS blockade, especially in
older patients with advanced NDD-CKD or those whose
kidney function has worsened on RAS blockade, has been
questioned because their use could potentially compromise
decline.3,4 However, this particular opinion was based on
observational data3,4 and conflicted with data from 2 other
studies.5,6 These data serve to highlight the controversy
surrounding the availability of satisfactory evidence or the
lack thereof regarding the safety of ACE-inhibitor or ARB
use in patients with advanced NDD-CKD.
The National Kidney Foundation–Kidney Disease Out-
comes Quality Initiative (NKF-KDOQI) publishes a series
of reports addressing controversial questions in
nephrology care for which evidence is lacking or contra-
dictory and precludes solid clinical practice guidance.
These topics are selected based on responses to surveys
posted on a physician-directed page on the KDOQI website
(https://www.kidney.org/professionals/guidelines). In a
2016 KDOQI survey, 53.8% of 703 respondents answered
“No,” whereas 46.2% responded “Yes” to the question:
“Should angiotensin converting enzyme inhibitors or
angiotensin receptor blockers be discontinued in patients
with non-dialysis dependent CKD once the eGFR drops
below 20 ml/min/1.73 m2?” This NKF-KDOQI contro-
versies report examines the available literature and reviews
current data on the relationship between RAS inhibition
and risk for kidney function decline in patients with
eGFRs < 30 mL/min/1.73 m2 who are not dialysis
dependent (referred to as “advanced CKD” in this article).
The report also discusses the available data in adults with
advanced CKD that address the impact of ACE inhibitors or
ARBs when used alone or in combination with mineralo-
corticoid receptor blockers on serum potassium levels. The
overall goal of this report is to provide a broad perspective
regarding the benefits and risks on renal outcomes of using
RAS inhibition in adults with advanced CKD, focusing on:
(1) initiation of RAS inhibition and (2) continuation or
withdrawal of RAS inhibition in patients previously using
these agents who have now progressed to advanced CKD.

AJKD Vol XX | Iss XX | Month 2018 1


RAS Inhibition and Risk for Renal Outcomes in
Advanced CKD
De Novo Initiation of RAS Inhibition
Although evidence supports the benefit of starting RAS
inhibition in the earlier stages of CKD for the prevention of
CKD progression, especially among patients with pro-
teinuria,5,7-9 few studies have directly tested the renal
benefit of RAS inhibition in the setting of advanced CKD
(when eGFR decreases to <30 mL/min/1.73 m2 or serum
creatinine is >2.0 mg/dL), making their use controversial
in this patient population. We summarize the data on the
initiation of RAS inhibition and its effect on renal out-
comes among observational studies and trials of patients
with CKD, with a focus on the data in advanced CKD when
available.
One of the only trials dedicated to the study of ACE-
inhibitor treatment initiation in patients with advanced
CKD and without diabetes mellitus was conducted by Hou
et al6 in China. The study included 2 groups: 104 partic-
ipants in group 1 with a serum creatinine level of 1.5 to
3.0 mg/dL treated with benazepril, 20 mg/d and 224
participants in group 2 with a serum creatinine level of 3.1
to 5.0 mg/dL randomly assigned to receive either bena-
zepril, 20 mg/d or placebo. All patients had not received
ACE inhibitors for at least 6 weeks before screening. In this
trial, benazepril was found to be superior to placebo in
delaying the composite outcome of doubling of serum
creatinine level, end-stage renal disease (ESRD), or death
among those with a baseline serum creatinine level be-
tween 3.1 and 5.0 mg/dL (group 2). However, more
participants in group 2 (serum creatinine, 3.1-5.0 mg/dL)
who were randomly assigned to benazepril treatment
reached the primary end point compared with those with
serum creatinine levels < 3.0 mg/dL (group 1), and the
authors suggested that the benefit of ACE inhibition
may be maximized if used during the earlier stages of
NDD-CKD. No differences were noted in BP in the 2 arms,
and no subgroup analysis was provided by baseline pro-
teinuria in this study.6 This trial is one of the few studies
to address the controversy regarding the benefits of the
initiation of RAS blockade monotherapy in patients with
advanced CKD, although the exact eGFRs of patients
included for study were not specified.
Other trials that have tested the effect of RAS inhibition
in adults with advanced CKD include the REIN (Ramipril
Efficacy in Nephrology) trial10 and AASK (African Amer-
ican Study of Kidney Disease and Hypertension)11
(Table 1). In a subgroup analysis of the REIN trial,
which randomly assigned participants to ramipril versus
placebo, the benefit of ACE inhibitors was noted to be
independent of the baseline kidney function, although
fewer participants had a creatinine clearance (CLcr) < 30
mL/min/1.73 m2 at enrollment.12 In AASK, which
included African American participants with hypertension-
attributed NDD-CKD, no benefit was derived from initia-
tion of ACE inhibitor treatment compared with either
2 AJKD Vol XX | Iss XX | Month 2018
Perspective
calcium channel blockers or β-blockers in delaying the
slope of decline in eGFR, but there was a statistically
significant interaction by baseline eGFR.11,13 Among
AASK participants with baseline eGFRs < 40 mL/min/
1.73 m2,11 the rate of eGFR decline was lower among
participants assigned to ramipril versus amlodipine treat-
ment.13 Both the REIN trial and AASK also demonstrated a
reduced risk for CKD progression among those assigned to
ACE-inhibitor treatment who had baseline proteinuria10,13
(Table 1). These data suggest that ACE-inhibitor mono-
therapy is renoprotective in patients with lower kidney
function, although the number of participants with
advanced CKD was limited.
Most trials of RAS blockade among patients with
diabetes mellitus have included patients with mild to
moderate severity of NDD-CKD14-18 (Table 1). In a post
hoc analysis of the RENAAL (Reduction of Endpoints in
Non-Insulin-Dependent Diabetes With the Angiotensin II
Antagonist Losartan) Study,17 the benefit of losartan on
ESRD risk was consistent across all levels of baseline eGFR.
In reference to our controversies question, this post hoc
analysis favors the initiation of ARB monotherapy in
advanced CKD, although the number of participants with
advanced CKD was limited.
In ONTARGET (Ongoing Telmisartan Alone and in
Combination with Ramipril Global Endpoint Trial), a
randomized controlled trial of ACE inhibitors, ARBs, or
their combination among patients with either vascular
disease or type 2 diabetes mellitus, no benefit was noted
among those receiving combination therapy as opposed to
monotherapy.18 No differences in risk for doubling of
serum creatinine level or long-term dialysis therapy were
noted among those with low eGFRs (Table 1). Few other
studies have examined the combination of ACE inhibitor
and ARB in the advanced CKD population with diabetes
mellitus. For example, VA NEPHRON-D (Veteran Affairs
Nephropathy in Diabetes Study), which randomly assigned
patients with diabetes mellitus to ACE-inhibitor plus ARB
therapy versus monotherapy included only patients with
baseline eGFRs > 30 mL/min/1.73 m2.19 In the HALT-
PKD (Halt Progression of Polycystic Kidney Disease) trial,
participants were randomly assigned to ACE-inhibitor and
ARB treatment compared to ACE inhibitor with placebo,
but no difference was noted in the progression of kidney
disease, and few participants had low eGFRs20 (Table 2).
Four observational studies have suggested that RAS in-
hibitor use in patients with advanced CKD, with or
without diabetes mellitus, slows eGFR decline compared to
nonuse21-23 (Table 1). In contrast, a prior nested case-
control study also noted that in a Canadian cohort of pa-
tients with diabetes mellitus, the risk for ESRD was 4-fold
higher among those who were receiving ACE inhibition
during long-term follow-up,24 although it is unclear what
the distribution of kidney function was at baseline among
these patients.
Because of the slowly progressive nature of CKD, most
of the studies that we highlight on this issue have used
 Table 1. Initiation of RAS Blockade and Risk for Renal Outcomes Among Trials and Observational Studies With Inclusion of Patients With Advanced CKD
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Perspective
Kidney Function Outcome Different
Inclusion Primary End by eGFR ≥ 30 Outcome Different
Study Population N F/U Comparison Criteria Point Outcome or <30 by Proteinuria
CKD Trials in Pts w/ DM
Mann et al18,53 TRANSCEND 1,629; 56 mo Telmisartan vs Scr < 3.0 Dialysis or No difference Interaction between Interaction by BL
(pts w/ high 49 w/ placebo doubling of overall CKD (eGFR < 60) albuminuria with
vascular risk or eGFR < 30 Scr vs no CKD w/ harm harm (HR 2.35) for
DM intolerant of in CKD group (HR, those with normal
ACE inhibitor) 1.38) albuminuria
Mann et al15 ONTARGET 5,623 56 mo Telmisartan, Scr < 3.0 Doubling of No benefit of dual No interaction No interaction by
(pts ≥ 55 y w/ ramipril, or both Scr or dialysis blockade; but in normal/mildly,
DM or vascular or death eGFR < 60 w/ moderately, or
disease) severely increased severely increased
albuminuria, albuminuria
primary renal end
point: HR, 1.63
(1.05-2.51)
Mann et al70 MICRO-HOPE 333 w/ 4.5 y Ramipril vs Scr < 2.3 Slope of No difference No difference No difference
(T2DM) Scr > 1.4 placebo change in Scr
Brenner et al8 RENAAL 1,417 3.4 y Losartan vs Scr 1.3-3.0 Doubling of 23% ↓ in ESRD No difference Not assessed
(pts w/ T2DM) placebo Scr, ESRD, risk in those w/
or death eGFR < 30
Maschio AIPRI (89% 583 3y Benazepril vs Scr 1.5-4 Doubling of Protection in those Yes, stratified by Yes; increased
et al71 w/ non-DM placebo Scr or ESRD in benazepril arm CLcr 30-45 vs 45-60 benefit for those
nephropathy; & ↑ benefit in those with > 1g/24 hr of
11% w/ DN) w/ CLcr > 45 proteinuria
Imai et al14 ORIENT (T2DM 577 4y Olmesartan vs Scr 1-2.5 Doubling of ↑ CV death in Not assessed Not assessed
Asian pts) placebo Scr, ESRD, olmesartan arm;
or death no difference in
composite renal outcomes
Lewis et al7 IDNT (T2DM, ??a 2.6 y Irbesartan vs Scr 1-3 Doubling of 33% ↓ in ARB arm Not assessed Not assessed
HTN, & amlodipine vs Scr, ESRD, vs placebo & 37%
proteinuria > placebo or death ↓ in ARB vs
900 mg/d) amlodipine
CKD Trials in Pts w/o DM
Agodoa et al13 AASK (HTN- 895 3y Metoprolol vs eGFR 20-65 50% decline No difference Yes, benefit in those Yes, benefit in those
attributed CKD) amlodipine vs in eGFR, w/ GFR < 40 at BL w/ UPCR > 0.22
ramipril ESRD, or
death
Ruggenenti REIN (non-DM 322 27 mo Ramipril vs CLcr 20-70 Rate of eGFR Benefit Rampiril was Yes, benefit in those
et al10,12 pts not treated placebo decline or beneficial for those w/ >3 g/d
w/ ACE inhibitor ESRD with proteinuria proteinuria
in 3 mo prior)
(Continued)
3
 Table 1 (Cont'd). Initiation of RAS Blockade and Risk for Renal Outcomes Among Trials and Observational Studies With Inclusion of Patients With Advanced CKD
4

Kidney Function Outcome Different

Inclusion Primary End by eGFR ≥ 30 Outcome Different
Study Population N F/U Comparison Criteria Point Outcome or <30 by Proteinuria
Hou et al6 Non-DM Chinese 422 3.4 y Group 1: Group 1: Scr Doubling of Benefit Yes; potentially Not assessed
CKD pts benazepril; group 1.5-3; group 2: Scr, ESRD, or worse renal
2: benazepril vs 3.1-5 death outcomes in those
placebo w/ advanced CKD
vs those w/ less
severe CKD
Bhandari STOP-ACE i 410 3y ACE inhibitor or eGFR < 30 Change in Study ongoing Not available Not available
et al26 (CKD4-5 on ARB eGFR
ACE inhibitor, monotherapy, or
ARB, or both) dual therapy vs
discontinuation
of therapy
Observational Studies
Hsu et al21 Hypertensive 28,497 7 mo ACE inhibitor/ Use of ≥1 Dialysis or Benefit (HR, 0.94; NA Not assessed
advanced CKD ARB users vs antihypertensive composite 0.91-0.97)
in Taiwan nonusers & Scr > 6 outcome of
dialysis &
death
Jovanovich HOST 1,099 3.2 y ACE inhibitor & CLcr < 30 Dialysis Benefit (HR, 0.81; NA Not assessed
et al22 (advanced CKD ARB use initiation 0.69-0.95)
or ESRD) or death
Suissa et al24 Canadian cohort 6,102 7.8 y ACE inhibitor use NA ESRD onset Harm (HR, 2.5; Not assessed Not assessed
of pts w/ DM 1.3-4.7)
Oh et al23 Korean pts w/ 2,067 16 mo ACE inhibitor/ eGFR < 30 ESRD onset Harm (HR, 1.38; NA No interaction
advanced CKD ARB users vs 1.11-1.73) (P = 0.14) by
nonusers proteinuria (but by
dipstick)
Abbreviations and definitions: ↓, reduction; ↑, greater; AIPRI, ACE Inhibition in Progressive Renal Insufficiency; AASK, African American Study of Kidney Disease and Hypertension; ACE, angiotensin-converting enzyme; ARB,
angiotensin receptor blocker; BL, baseline; CKD, chronic kidney disease: Clcr, creatinine clearance (in mL/min); CV, cardiovascular; DM, diabetes mellitus; DN, diabetic nephropathy; eGFR, estimated glomerular filtration rate (in mL/
min/1.73 m2); ESRD, end-stage renal disease; F/U, follow-up; HOST, Homocysteine in Kidney and End Stage Renal Disease; HR, hazard ratio (with 95% confidence interval when available); HTN, hypertension; IDNT, Irbesartan
Diabetic Nephropathy Trial; MICRO-HOPE, Microalbuminuria Cardiovascular Renal Outcomes - Heart Outcomes Prevention Evaluation; NA, not applicable; ONTARGET, Ongoing Telmisartan Alone and in Combination With Ramipril
Global Endpoint Trial; ORIENT, Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial; pts, patients; RAS, renin-angiotensin system; REIN, Ramipril Efficacy in Nephrology; RENAAL, Reduction of
Endpoints in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan; Scr, serum creatinine (in mg/dL); STOP-ACEi, Multi-Centre Randomised Controlled Trial of ACE Inhibitor/ARB Withdrawal in Advanced
Renal Disease; T2DM, type 2 diabetes mellitus; TRANSCEND, Telmisartan Randomized Assessment Study in ACEi Intolerant Subjects With Cardiovascular Disease; UPCR, urinary protein-creatinine ratio (in g/g).
AJKD Vol XX | Iss XX | Month 2018

a
Unknown.

Perspective
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Perspective
Table 2. Decline in Kidney Function After Initiation of RAS Inhibitors
Kidney
Function
Inclusion
Study Population N F/U Comparison Time Frame Criteria Primary End Point Outcome
Post Hoc Analyses of RCTs
Mann et al53 TRANSCEND (pts w/ 5,926 56 mo Telmisartan vs 6 wk Scr < 3.0 Composite of MI, Decline in eGFR in first 6 mo
high vascular risk or placebo stroke, CV death not associated with
DM intolerant of ACE composite CV outcome
inhibitor)
Clase et al51 ONTARGET & 9,340 56 mo Telmisartan, 2 & 8 wk after ACE Scr < 3.75 Doubling of Scr or ≥15% decline in eGFR
TRANSCEND ramipril, or their inhibitor initiation dialysis; CV associated w/ trend to higher
combination or outcomes risk for CV outcomes; not
placebo associated w/ renal outcomes
Bakris et al45 12 RCTs 1,102 3y Increases in Scr W/in 6 mo post All levels ESRD or change >30% increase in Scr
ACE inhibitor in GFR
initiation
Holtkamp et al5 RENAAL (T2DM) 1,417 3.4 y Losartan vs W/in 3 mo of start Scr 1.3-3.0 Doubling of Scr, Slower long-term eGFR
placebo of treatment ESRD, or death decline if larger initial decline
in eGFR
Ku et al52 AASK 899 11.1 y Ramipril vs 12-16 wk post GFR 20-65 ESRD Decline in eGFR not
amlodipine or ACE inhibitor associated w/ worsened
metoprolol initiation outcomes by antihypertensive
agent assignment (ACE
inhibitor vs not)
Observational Studies
Hirsch et al72 Mostly African 48 6y ACE inhibitor use 12 mo post ACE Scr > 1.4 ESRD or change No difference by >30% vs
American pts inhibitor initiation in eGFR slope < 30% decline in kidney
function initially
Schmidt et al54 Observational; UK 122,363 17 y ACE inhibitor/ARB 12 mo post ACE Excluded HF, MI, ESRD, or >10% increase in Scr
primary care initiation inhibitor/ARB those with death associated w/ risk for all
initiation ESRD outcomes
Abbreviations and definitions: ↓, reduction; ↑, greater; AASK, African American Study of Kidney Disease and Hypertension; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CV, cardiovascular; DM, diabetes
mellitus; eGFR, estimated glomerular filtration rate (in mL/min/1.73 m2); ESRD, end-stage renal disease; F/U, follow-up; HF, heart failure; MI, myocardial infarction; ONTARGET, Ongoing Telmisartan Alone and in Combination With
Ramipril Global Endpoint Trial; pts, patients; RAS, renin-angiotensin system; RCT, randomized controlled trials; RENAAL, Reduction of Endpoints in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan; Scr,
serum creatinine (in mg/dL); T2DM, type 2 diabetes mellitus; TRANSCEND, Telmisartan Randomized Assessment Study in ACEi Intolerant Subjects With Cardiovascular Disease; UK, United Kingdom.
5

combined end points (50% decline in kidney function or
death) or change in various measures of kidney function as
outcomes of interest (Table 1). Thus, they have not been
able to provide more solid evidence of the risk for ESRD
(as a sole and hard outcome) with longer-term use of RAS
inhibition (eg, over decades).
Continuation Versus Withdrawal of RAS Inhibition
Among Patients Already Receiving RAS Inhibition
The majority of the available data derived from clinical
trials that we have reviewed to date are focused on the
question of whether RAS blockade should be initiated
among patients with advanced CKD. However, there are
fewer studies that address the question of when and
whether those patients who are already receiving RAS
inhibition should have these agents continued (or
discontinued) in the setting of advanced CKD. We believe
it is prudent to avoid extrapolating evidence from trials
and observational studies focused on outcomes after RAS
blockade initiation to the management of patients who are
already receiving RAS inhibition who have advancing CKD
and hence discuss this issue here separately.
In our anecdotal experience, many providers discon-
tinue RAS inhibition in the setting of severely reduced
kidney function (eg, when eGFR declines below 15-
20 mL/min/1.73 m2) due to a variety of considerations,
including concerns regarding hyperkalemia, expectation of
hemodynamic improvements in kidney function with RAS-
inhibitor cessation (and therefore gain of additional time
for the placement and maturation of dialysis access), and
response to AKI events that may occur during this vulner-
able period. To date, there is little trial-grade evidence to
guide this issue. In a small trial of patients with CKD
(CLcr < 60 mL/min/1.73 m2), an improvement in CLcr
from 33 to 43 mL/min/1.73 m2 was observed in those
randomly assigned to a 50% reduction in ACE-inhibitor or
ARB dose compared with those with no dose reduction,
although it is unclear how many patients with advanced
CKD were included.25 We recommend caution in extrap-
olating data from RAS blockade–naive patients with
advanced CKD to those who have received RAS blockade in
the past and have progressively lost kidney function.
An ongoing randomized controlled trial (STOP-ACEi
[Multi-Centre Randomised Controlled Trial of ACE inhib-
itor/ARB Withdrawal in Advanced Renal Disease]) of
stopping (vs continuing) RAS blockade should provide
additional data on the risks and benefits of RAS blockade
on kidney disease progression in patients with advanced
CKD and diabetes mellitus.26 STOP-ACEi will be an open-
label randomized controlled trial of 410 participants with
CKD stage 4 or 5 who are currently receiving RAS inhi-
bition. Participants will be randomly assigned in 1:1
fashion to discontinuation of treatment with all ACE in-
hibitors or ARBs versus continuation of the current RAS
regimen for 3 years, with the primary outcome being the
difference in kidney function at 3 years. The strengths of
this trial include the focus on the advanced CKD
6 AJKD Vol XX | Iss XX | Month 2018
Perspective
population and the novelty of the data it will provide, but
weaknesses include the inclusion of patients with slowly
progressive declines in kidney function (inclusion of pa-
tients with eGFR decline of just >2 mL/min/1.73 m2 in
the 24 months preceding enrollment), lack of use of a hard
outcome such as ESRD as the primary outcome of interest,
and the potential imbalances in the competing risk for
mortality that may occur with the 2 alternate strategies.
While we await results of STOP-ACEi, we highlight some
of the limited observational data that have investigated the
role of RAS treatment continuation (vs cessation) in
advanced CKD. One small observational study previously
demonstrated that the rate of eGFR decline was slower
among participants with advanced CKD who had treatment
with ACE inhibitors or ARBs withdrawn.27 This study
suggested that patients with more rapid decline in kidney
function during the advanced stages of CKD benefited from
RAS inhibitor withdrawal and were observed to experience
a delay in the need for renal replacement therapy compared
with those who continued RAS inhibition.27 In addition, in
an observational study of 100 patients with advanced CKD,
patients who were already receiving ACE-inhibitor/ARB
therapy and had a 25% increase in their serum creatinine
levels over baseline values during follow-up who
discontinued RAS blockade were observed to have im-
provements in kidney function.3,4 This has led some to
advocate for the discontinuation of RAS inhibition in the
setting of worsening kidney function with advanced
CKD among those who are already on RAS inhibition.28,29
Conclusions Regarding RAS Inhibition and Risk for
Renal Outcomes in Advanced CKD
Given the totality of the current evidence in addressing our
controversies question, we suggest that ACE-inhibitor or
ARB monotherapy initiation appears to be beneficial in
patients with advanced CKD in the absence of diabetes
mellitus, especially among those with proteinuria. How-
ever, evidence is more limited among patients with
advanced CKD and diabetes mellitus given the traditional
exclusion of many patients with advanced CKD from dia-
betes trials.30 More studies are needed to confirm the
benefit of RAS blockade monotherapy initiation in patients
with diabetes mellitus and advanced CKD (Box 1).
Regarding the risks versus benefits of continuing RAS
inhibition in advanced CKD, we suggest that in the setting
of hypotension or repeated episodes of AKI, cessation of
treatment with these agents seems reasonable. Whether
stopping treatment with these agents routinely in patients
with advanced CKD who experience rapid declines in
kidney function will slow the progression to renal
replacement therapy is unclear.
RAS Inhibition and Risk for Cardiovascular
Mortality in Advanced CKD
Although a number of trials have demonstrated the benefit
of RAS inhibition on cardiovascular (CV) outcomes,31-33
Perspective
Box 1. Recommendations for Future Research Among Patients
With Advanced CKD
• Prospective randomized controlled trial testing RAS inhibition
against alternative agents (such as nondihydropyridine cal-
cium channel blockers) in advanced CKD, especially among
patients with diabetes for both CV and renal outcomes.
• Studies that inform how to best individualize therapy among
patients with advanced CKD based on heterogeneity in the
treatment response by factors such as age, race, cause of
CKD, comorbid conditions.
• Prospective trials to examine whether hyperkalemia mitiga-
tion will permit use of RAS inhibition in patients with
advanced CKD with hard end points such as kidney disease,
CV outcomes, or death.
• Studies that identify thresholds of concern for adverse renal
outcomes as it relates to acute declines in kidney function
during RAS inhibition initiation or continuation and hyper-
kalemia, especially in the setting of advanced diabetic kidney
disease.
• Prospective trials of RAS inhibition in advanced CKD among
patients who are older, are nonproteinuric, or with a history of
rapid kidney function decline and acute kidney injury.
Abbreviations: CKD, chronic kidney disease; CV, cardiovascular; RAS, renin-
angiotensin system.
few trials have been devoted to the study of RAS inhibition
and CV outcomes in adults with advanced CKD. The ma-
jority of trials that have assessed the benefit of ACE in-
hibitors or ARBs on CV outcomes have included a subset of
participants with mild NDD-CKD and tested for effect
modification by CKD status. Of trials that have shown a
benefit from RAS inhibition,34-36 no effect modification by
the presence or absence of NDD-CKD (eGFR < 60 mL/
min/1.73 m2) was noted, although in 2 trials, the benefit
of ACE inhibitors tended to be greater among those
with NDD-CKD.36,37 A few trials have failed to show a
difference in CV outcomes in patients receiving RAS
inhibition compared to placebo, and results did not differ
among those with NDD-CKD.18,37,38 However, a major
limitation to these studies is the lack of sufficient number
of participants with advanced CKD and lack of data for
proteinuria.
A number of meta-analyses have focused on the role of
RAS inhibition on risk for CV outcomes and shown the
benefit of RAS inhibition, especially ACE inhibitors
(as compared to ARB therapy).39,40 However, to our
knowledge, few studies have examined this question in the
advanced CKD population.
In summary, evidence to address the effect of RAS in-
hibition on CV outcomes in patients with advanced CKD is
lacking, and as such, there is insufficient data to provide
definitive guidance regarding this controversy. Most of the
data currently available are derived from studies of patients
with mild to moderate NDD-CKD, and the inclusion of
patients with more advanced NDD-CKD in future trials of
interventions to assess CV outcomes is needed (Box 1).
AJKD Vol XX | Iss XX | Month 2018
Declines in Kidney Function With Initiation of
RAS Inhibition in Advanced CKD
Although ACE inhibitors and ARBs are known to suppress
proteinuria, their treatment initiation is also commonly
associated with increases in serum creatinine levels, which
are commonly ascribed to hemodynamic changes and
thought to be benign.41-44 Traditionally, tolerance of up to
a 30% increase in serum creatinine level after the initiation
of ACE-inhibitor or ARB treatment has been recom-
mended.45,46 However, this recommendation was based
primarily on data from trials that excluded patients with
advanced CKD. The prevalence of RAS inhibition use de-
creases with advancing NDD-CKD stages.47,48 A recent
pilot study of combination ACE-inhibitor and ARB use in
adults with advanced CKD demonstrated that almost half
could not tolerate dual ACE-inhibitor and ARB therapy due
to significant declines in kidney function or the onset of
hyperkalemia.49
Post hoc analyses of a few randomized controlled trials
(AASK, ONTARGET, TRANSCEND [Telmisartan Random-
ized Assessment Study in ACEi Intolerant Subjects With
Cardiovascular Disease], and RENAAL) have not shown
that acute declines in kidney function occurring within 6
months of initiating RAS blockade are associated with
higher risk for kidney function decline and ESRD, even if
the magnitude of the kidney function decline is greater
than 15% to 20%.5,50-53 In AASK, these results did not
differ by baseline eGFR or level of proteinuria.52 In
ONTARGET, acute declines in eGFR were associated with a
non–statistically significant tendency toward higher risk
for CV outcomes (Table 2).51 However, caution should be
used in the interpretation of these studies given their post
hoc design and the lack of data regarding long-term ESRD
risk in the majority of such studies.
In an observational study, Schmidt et al54 in the United
Kingdom recently demonstrated that declines in eGFR
even as small as 10% within the first 12 months after RAS
inhibition are associated with higher risk for adverse
outcomes, including ESRD. However, results of this study
should also be interpreted with caution given the longer
time frame over which these acute declines in eGFR were
assessed. These declines in eGFR may not necessarily be
related to RAS inhibition, but may reflect CKD progression
and/or selection bias.
Based on the currently available evidence, it does not
appear that eGFR decline after RAS blockade is strongly
associated with risk for adverse renal or CV outcomes
based on post hoc secondary analyses of trial-grade data. In
addition, whether concomitant interventions, including
intensive BP lowering with RAS blockade, may predispose
to a higher risk for adverse kidney outcomes has not been
thoroughly investigated. Based on observational and post
hoc analyses,52,54 we suggest that acute (within 12 weeks
after initiation of RAS inhibition) declines in eGFR > 20%
may warrant caution and consideration of cessation of
therapy. However, limitations of the available evidence
7

support the need for more clinical trials that directly
address our controversies question (Box 1).
RAS Inhibition and Risk for Hyperkalemia
Nondiabetic Advanced CKD
Several clinical trials provide data to help gauge the risk for
hyperkalemia in patients with advanced CKD who do not
have diabetes (Table 3). For example, the REIN trial randomly
assigned patients with CLcr of 20 to 70 mL/min/1.73 m2 to
receive ramipril (up to 5 mg daily) versus placebo to achieve
a goal diastolic BP ≤ 90 mm Hg.12 Among participants with
the lowest tertile of kidney function, only 2 in the ramipril
arm and 1 in the placebo arm were taken off the study
medication due to persistent hyperkalemia despite recom-
mended dietary changes, diuretic therapy, and balancing
acid-base status. In this lowest tertile of kidney function,
potassium levels were significantly higher in the ramipril
group compared to placebo, but not by more than a mean of
0.5 mmol/L. Similar findings were reproduced in another
trial: even after dose titration of benazepril in patients with
advanced CKD, the development of hyperkalemia, defined as
potassium level ≥ 5.6 mmol/L, was a rare event.6
In another Chinese trial, 360 hypertensive patients with
serum creatinine levels between 1.5 and 5.0 mg/dL and
mean eGFR of w30 mL/min/1.73 m2 were treated with
either benazepril or losartan.55 Hyperkalemia, defined as
serum potassium level ≥ 5.6 mmol/L during the pretitra-
tion phase and ≥6 mmol/L during the treatment phase,
developed in 8 of 180 patients using benazepril and 8 of
180 patients using losartan, although the number of par-
ticipants with advanced CKD was not described. Six of these
16 patients had successful optimization of serum potassium
levels with diuretics and dietary potassium restriction, and
the other 10 patients withdrew from the study due to
persistent hyperkalemia. Analysis from an observational
study that evaluated ACE-inhibitor or ARB therapy in par-
ticipants with advanced CKD found that although such
therapy increased the risk for hyperkalemia, it did not
translate into increased risk for predialysis mortality.21
In summary, the evidence addressing the safety aspect
of our controversies question suggests a definite increase in
risk for hyperkalemia in patients with advanced CKD and
no diabetes mellitus. However, in many of these studies,
despite the increased risk for hyperkalemia with RAS
blockade initiation, there was a consistent reduction in
risk for progressive loss of kidney function and incident
ESRD. Thus, the evidence suggests that initiation of RAS
blockade monotherapy may be useful despite the addi-
tional safety monitoring that may be required in patients
with advanced CKD. Hyperkalemia prevention and man-
agement protocols used in these studies include dietary
potassium restriction, correction of acid-base imbalances,
avoidance of concomitant use of medications that promote
hyperkalemia, optimization of diuretic use, and use of
cation-exchange resins when clinically indicated.46
8 AJKD Vol XX | Iss XX | Month 2018
Perspective
Advanced CKD Due to Diabetes Mellitus
There are no major clinical trials of RAS blockade focused
exclusively on patients with advanced CKD due to diabetic
nephropathy (Table 3). Two studies that enrolled patients
with eGFRs ≤ 30 mL/min/1.73 m2 were the RENAAL
Study7 and IDNT (Irbesartan Diabetic Nephropathy Trial).8
Many other clinical trials, including MARVAL (Micro-
albumin Reduction with Valsartan), IRMA-2 (Irbesartan in
Patients With Type 2 Diabetes and Microalbuminuria), VA
NEPHRON-D, TRANSCEND, and ONTARGET, excluded
patients with eGFRs < 30 mL/min/1.73 m2.15,19,56-63
RENAAL Study participants were randomly assigned to
receive losartan titrated up to 100 mg daily versus placebo
in addition to other necessary antihypertensive medica-
tions to achieve a target BP < 140/90 mm Hg
(Table 3).8,64 The lowest baseline eGFR among all
participants was 34.4 ± 12.0 mL/min/1.73 m2. Hyper-
kalemia resulted in the discontinuation of study medica-
tion in 1.1% of patients in the losartan group versus 0.5%
in the placebo group. Post hoc analysis demonstrated that
38.4% of patients in the losartan group had serum potas-
sium levels ≥ 5.0 mmol/L at 6 months compared to 22.8%
in the placebo group (P < 0.001); 10.8% in the losartan
group and 5.1% in the placebo group had serum potas-
sium levels ≥ 5.5 mmol/L. Losartan therapy was associated
with significantly higher risk for hyperkalemia at 6
months. Incident hyperkalemia was predictive of a 22%
higher risk for the composite end point of doubling of
serum creatinine level or ESRD.65 However, we caution
that evidence from the RENAAL trial may not be general-
izable to all patients with advanced CKD given the low
number of enrollees with more advanced disease.8
In IDNT,7 patients were randomly assigned to receive
irbesartan, 300 mg, daily versus amlodipine, 10 mg, daily
versus placebo in addition to other antihypertensive
medications to target BP < 135/85 mm Hg. The lowest
eGFR at study enrollment was 15 mL/min/1.73 m2 for
women and 20 mL/min/1.73 m2 for men by both
CKD-EPI (CKD Epidemiology Collaboration) and MDRD
(Modification of Diet in Renal Disease) Study
equation–based calculations. Eleven of 579 patients using
irbesartan versus 3 of 567 using amlodipine and 2 of 569
patients using placebo (P = 0.01) developed hyperkalemia,
which led to cessation of the randomized intervention.
In summary, both the RENAAL Study and IDNT focused
on patients with mild to moderate NDD-CKD and demon-
strated a small but statistically significant risk for developing
hyperkalemia sufficient to stop the ARB monotherapy.
These adverse effects of ARB monotherapy were offset by a
20% risk reduction of the primary end point of doubling of
serum creatinine level, ESRD, or death with ARB use.7
However, it must be emphasized that these trials included
patients with diabetes mellitus, a group at higher risk for
hyperkalemia. Not all patients with diabetes may be at the
same risk for hyperkalemia because subphenotypes, such as
those with type 4 renal tubular acidosis, may be at greater
 Table 3. Hyperkalemia With Initiation of Renin-Angiotensin Inhibition in Patients With CKD
AJKD Vol XX | Iss XX | Month 2018

Perspective
Kidney
Function
Inclusion Primary End
Study Population N F/U Comparison Criteria Point Outcome
Diabetic CKD Trials With Renin-Angiotensin Inhibition Monotherapy
Brenner RENAAL (T2DM, 1,513 3.4 y Losartan potassium Scr 1.3-3.0 Doubling of 38.4% pts on losartan vs 22.8% on placebo had
et al8,64,65 nephropathy, vs placebo Scr, ESKD, or K+ ≥ 5.0 at 6 mo (P < 0.001), 10.8% on losartan &
ACR ≥ 300 mg/g) death 5.1% on placebo had K+ ≥ 5.5; losartan associated
w/ significantly ↑ risk for hyperkalemia (OR, 2.8) at
6 mo; incident hyperkalemia predictive of ↑ risk
(HR, 1.22) of composite end point of Scr doubling
or ESKD
Lewis et al7 IDNT (T2DM, HTN, 1,715 2.6 y Irbesartan vs Scr 1.2-3.0 Doubling of 11/579 pts on irbesartan, 3/567 pts on amlodipine
proteinuria > 900 mg/d) amlodipine vs placebo (♂), 1.0-3.0 Scr, ESKD, or (P = 0.01), & 2/569 pts on placebo (P = 0.01) had
(♀) all-cause hyperkalemia leading to stopping therapy
mortality
Nondiabetic CKD Trials With Renin-Angiotensin Inhibition Monotherapy
Ruggenenti REIN post hoc analysis 322 3.4 y Ramipril to achieve CLcr 20-70 Composite of In the lowest tertile, ΔK+ significantly ↑ in ramipril vs
et al12 (CLcr 20-70, persistent DBP < 90 mm Hg vs (eGFR doubling of Scr, placebo group but was never >0.5
proteinuria > 1,000 mg/d) placebo lowest ESKD, or death
tertile, 10.5-
32.7)
Hou et al6 Non-DM Chinese CKD pts 402 3.4 y Group 1: benazepril Scr 1.50- Composite of K+ > 6.0 reported in 2/104 pts in group 1, in 6/112
(group 1: Scr 1.5-3.0, w/ no placebo; group 5.0 & CLcr doubling of Scr, of group 2 benazepril arm, & in 5/112 of group 2
group 2: Scr 3.1-5.0 & 2: benazepril vs 20-70 ESKD, or death placebo arm; persistent hyperkalemia led to w/
persistent proteinuria > placebo drawal of 2 pts from group 2 benazepril arm & 1 pt
300 mg/d) from group 2 placebo arm
Hou et al55 ROAD (Scr 1.50-5.0, CLcr 360 3.7 y Benazepril (group 1) Scr 1.50- Composite of Hyperkalemia (K+ > 5.6 in pretitration phase & >6.0
20-70, persistent vs benazepril 5.0 & CLcr doubling of Scr, in treatment phase) in 8/180 (4.4%) of pts on
proteinuria > 300 mg/d) uptitration (group 2); 20-70 ESKD, or death benazepril & 8/180 (4.4%) on losartan: 3 in group
losartan (group 3) vs 1, 5 in group 2, 3 in group 3, 5 in group 4;
losartan uptitration hyperkalemia led to withdrawal of 10 pts
(group 4)
Hsu et al21 Prospective cohort (stable 28,497 27,678 ACE inhibitor/ARB Scr > 6.0 Initiation of 31% ↑ risk of hyperkalemia-related hospitalization
hypertensive anemic NDD- p-y users vs nonusers RRT & all- in users vs nonusers (P < 0.001); incidences of
CKD5 pts started on ESA, cause mortality 9.2% in users vs 6.7% in nonusers (P < 0.001); no
53% had DM) increase in predialysis mortality (P = 0.3)
Bhandari STOP-ACEi (CKD4-5 on 410 3y ACE inhibitor or ARB eGFR < 30 Change in Study ongoing
et al26 ACE inhibitor, ARB, or monotherapy, or dual eGFR
both) therapy vs
discontinuation of
therapy
Abbreviations and definitions: ↑, greater; ΔK+, change in serum potassium; ACE, angiotensin-converting enzyme; ACR, albumin-creatinine ratio; ARB, angiotensin II AT1 receptor blocker; CKD, chronic kidney disease; CLcr, creatinine
clearance (in mL/min/1.73 m2); DBP, diastolic blood pressure; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate (in mL/min/1.73 m2); ESA, erythropoiesis-stimulating agent; ESKD, end-stage kidney disease; F/U,
follow-up; HR, hazard ratio; HTN, systemic arterial hypertension; IDNT, Irbesartan Diabetic Nephropathy Trial; K+, serum potassium (in mmol/L); NDD-CKD, non–dialysis-dependent chronic kidney disease; OR, odds ratio; pts,
patients; REIN, Ramipril Efficacy in Nephrology; RENAAL, Reduction of Endpoints in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan; ROAD, Renoprotection of Optimal Antiproteinuric Doses; RRT, renal
replacement therapy; Scr, serum creatinine (in mg/dL); STOP-ACEi, Multi-Centre Randomised Controlled Trial of ACE inhibitor/ARB Withdrawal in Advanced Renal Disease; T2DM, type 2 diabetes mellitus.
9

risk. More clinical trials are required to directly establish the
risk-benefit balance of ACE-inhibitor or ARB monotherapy
in adults with diabetes and advanced CKD. Given the
availability and tolerability of newer potassium-binding
agents such as patiromer66,67 and sodium zirconium
cyclosilicate,68,69 which have both favorable efficacy and
safety profiles among patients with hyperkalemia receiving
RAS inhibition, we believe that hyperkalemia will be less
likely to limit the initiation or continuation of RAS inhibi-
tion among patients with CKD in the future.
Conclusions
We have carefully reviewed the available evidence from
clinical trials regarding the use of RAS blockade in patients
with advanced CKD. There is clearly more information
available with regard to patients with advanced CKD with
versus without diabetes mellitus. Current evidence suggests
that declines in eGFRs or increases in serum potassium
levels after RAS blockade are not associated with higher risk
for adverse renal outcomes. However, available clinical trial
data may not be generalizable to patients with advanced
CKD due to diabetes mellitus. Moreover, individual patients
may respond differently to RAS inhibition. Given these
controversies, individualization of treatment plans with
careful assessment of the risk to benefit ratio of RAS inhi-
bition should be the principle on which we consider the use
of these important medications with regard to their benefits
on CKD progression. We encourage providers to consider
factors such as patient age, degree of proteinuria suppres-
sion with RAS initiation, historical and prospective occur-
rence of AKI, and rate of kidney function decline when
making decisions surrounding the initiation, avoidance,
continuation, or discontinuation of RAS inhibition in pa-
tients with advanced CKD. In our opinion, we believe that
among patients with large acute declines in eGFR after RAS
blockade initiation (eg, >20%) without substantial sup-
pression of proteinuria, discontinuation of RAS blockade
may be considered. Patients with hypotension, AKI, or
rapid loss of kidney function may also warrant avoidance or
discontinuation of RAAS blockade. In the setting of the
availability of newer potassium agents, we do not believe
that increases in serum potassium levels should lead to
discontinuation of RAS blockade unless the hyperkalemia is
refractory to treatment with either diuretics, binders, or
their combination. Our recommendations for areas needing
additional research are listed in Box 1. Further studies are
needed to inform how providers should individualize
treatment decisions among patients with advanced CKD.
Article Information
Authors’ Full Names and Academic Degrees: Matthew R. Weir,
MD, Jay I. Lakkis, MD, Bernard Jaar, MD, Michael V. Rocco MD,
Michael J. Choi, MD, Holly Mattrix-Kramer, MD, MPH, and Elaine Ku,
MD, MAS.
Authors’ Affiliations: Division of Nephrology, Department of
Medicine, University of Maryland, School of Medicine, Baltimore,
10
Perspective
MD (MRW); University of Hawaii John A. Burns School of
Medicine, Honolulu, HI (JIL); Division of Nephrology, Department
of Medicine, Johns Hopkins University School of Medicine,
Baltimore, MD (BJ, MJC); Division of Nephrology, Department of
Medicine, Wake Forest University School of Medicine, Winston-
Salem, NC (MVR); Division of Nephrology and Hypertension,
Department of Public Health Sciences and Medicine, Loyola
University Chicago Stritch School of Medicine, Maywood, IL
(HMK); and Division of Nephrology, Department of Medicine,
University of California San Francisco, San Francisco, CA (EK).
Address for Correspondence: Matthew R. Weir, MD, Division of
Nephrology, University of Maryland School of Medicine, 22 S
Greene St, Rm N3W143, Baltimore, MD 21201. E-mail: mweir@
som.umaryland.edu
Support: There was no direct financial support for the preparation of
this article. Dr Ku was supported by National Institutes of Health
grant HL 131023. Dr Weir is supported by U01DK116095-01,
R01DK066013, R01HL127422, R01HL132372-01A1, and U01
DK1061022.
Financial Disclosure: Dr Weir serves on the Scientific Advisory
Board for Relypsa, Vifor, and Astra Zeneca. The remaining authors
declare that they have no relevant financial interests.
Other Disclosures: Dr Rocco is Chair of KDOQI. Dr Kramer is
KDOQI Vice Chair for Controversies and Commentaries and is
President-Elect of the NKF. Dr Choi is President of the NKF.
Dr Jaar is the KDOQI Vice Chair for Education.
Acknowledgements: We acknowledge the NKF for encouraging
the development of this article.
Peer Review: Received December 14, 2017. Evaluated by 3 external
peer reviewers, with direct editorial input from an Associate Editor,
who served as Acting Editor-in-Chief. Accepted in revised form
June 8, 2018. The involvement of an Acting Editor-in-Chief was to
comply with AJKD’s procedures for potential conflicts of interest
for editors, described in the Information for Authors & Journal
Policies.
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AJKD Vol XX | Iss XX | Month 2018