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

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RAS Inhibition and Risk for Renal Outcomes in calcium channel blockers or β-blockers in delaying the
Advanced CKD slope of decline in eGFR, but there was a statistically
significant interaction by baseline eGFR.11,13 Among
De Novo Initiation of RAS Inhibition AASK participants with baseline eGFRs < 40 mL/min/
Although evidence supports the benefit of starting RAS 1.73 m2,11 the rate of eGFR decline was lower among
inhibition in the earlier stages of CKD for the prevention of participants assigned to ramipril versus amlodipine treat-
CKD progression, especially among patients with pro- ment.13 Both the REIN trial and AASK also demonstrated a
teinuria,5,7-9 few studies have directly tested the renal reduced risk for CKD progression among those assigned to
benefit of RAS inhibition in the setting of advanced CKD ACE-inhibitor treatment who had baseline proteinuria10,13
(when eGFR decreases to <30 mL/min/1.73 m2 or serum (Table 1). These data suggest that ACE-inhibitor mono-
creatinine is >2.0 mg/dL), making their use controversial therapy is renoprotective in patients with lower kidney
in this patient population. We summarize the data on the function, although the number of participants with
initiation of RAS inhibition and its effect on renal out- advanced CKD was limited.
comes among observational studies and trials of patients Most trials of RAS blockade among patients with
with CKD, with a focus on the data in advanced CKD when diabetes mellitus have included patients with mild to
available. moderate severity of NDD-CKD14-18 (Table 1). In a post
One of the only trials dedicated to the study of ACE- hoc analysis of the RENAAL (Reduction of Endpoints in
inhibitor treatment initiation in patients with advanced Non-Insulin-Dependent Diabetes With the Angiotensin II
CKD and without diabetes mellitus was conducted by Hou Antagonist Losartan) Study,17 the benefit of losartan on
et al6 in China. The study included 2 groups: 104 partic- ESRD risk was consistent across all levels of baseline eGFR.
ipants in group 1 with a serum creatinine level of 1.5 to In reference to our controversies question, this post hoc
3.0 mg/dL treated with benazepril, 20 mg/d and 224 analysis favors the initiation of ARB monotherapy in
participants in group 2 with a serum creatinine level of 3.1 advanced CKD, although the number of participants with
to 5.0 mg/dL randomly assigned to receive either bena- advanced CKD was limited.
zepril, 20 mg/d or placebo. All patients had not received In ONTARGET (Ongoing Telmisartan Alone and in
ACE inhibitors for at least 6 weeks before screening. In this Combination with Ramipril Global Endpoint Trial), a
trial, benazepril was found to be superior to placebo in randomized controlled trial of ACE inhibitors, ARBs, or
delaying the composite outcome of doubling of serum their combination among patients with either vascular
creatinine level, end-stage renal disease (ESRD), or death disease or type 2 diabetes mellitus, no benefit was noted
among those with a baseline serum creatinine level be- among those receiving combination therapy as opposed to
tween 3.1 and 5.0 mg/dL (group 2). However, more monotherapy.18 No differences in risk for doubling of
participants in group 2 (serum creatinine, 3.1-5.0 mg/dL) serum creatinine level or long-term dialysis therapy were
who were randomly assigned to benazepril treatment noted among those with low eGFRs (Table 1). Few other
reached the primary end point compared with those with studies have examined the combination of ACE inhibitor
serum creatinine levels < 3.0 mg/dL (group 1), and the and ARB in the advanced CKD population with diabetes
authors suggested that the benefit of ACE inhibition mellitus. For example, VA NEPHRON-D (Veteran Affairs
may be maximized if used during the earlier stages of Nephropathy in Diabetes Study), which randomly assigned
NDD-CKD. No differences were noted in BP in the 2 arms, patients with diabetes mellitus to ACE-inhibitor plus ARB
and no subgroup analysis was provided by baseline pro- therapy versus monotherapy included only patients with
teinuria in this study.6 This trial is one of the few studies baseline eGFRs > 30 mL/min/1.73 m2.19 In the HALT-
to address the controversy regarding the benefits of the PKD (Halt Progression of Polycystic Kidney Disease) trial,
initiation of RAS blockade monotherapy in patients with participants were randomly assigned to ACE-inhibitor and
advanced CKD, although the exact eGFRs of patients ARB treatment compared to ACE inhibitor with placebo,
included for study were not specified. but no difference was noted in the progression of kidney
Other trials that have tested the effect of RAS inhibition disease, and few participants had low eGFRs20 (Table 2).
in adults with advanced CKD include the REIN (Ramipril Four observational studies have suggested that RAS in-
Efficacy in Nephrology) trial10 and AASK (African Amer- hibitor use in patients with advanced CKD, with or
ican Study of Kidney Disease and Hypertension)11 without diabetes mellitus, slows eGFR decline compared to
(Table 1). In a subgroup analysis of the REIN trial, nonuse21-23 (Table 1). In contrast, a prior nested case-
which randomly assigned participants to ramipril versus control study also noted that in a Canadian cohort of pa-
placebo, the benefit of ACE inhibitors was noted to be tients with diabetes mellitus, the risk for ESRD was 4-fold
independent of the baseline kidney function, although higher among those who were receiving ACE inhibition
fewer participants had a creatinine clearance (CLcr) < 30 during long-term follow-up,24 although it is unclear what
mL/min/1.73 m2 at enrollment.12 In AASK, which the distribution of kidney function was at baseline among
included African American participants with hypertension- these patients.
attributed NDD-CKD, no benefit was derived from initia- Because of the slowly progressive nature of CKD, most
tion of ACE inhibitor treatment compared with either of the studies that we highlight on this issue have used

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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).
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a
Unknown.

Perspective
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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
Perspective

combined end points (50% decline in kidney function or population and the novelty of the data it will provide, but
death) or change in various measures of kidney function as weaknesses include the inclusion of patients with slowly
outcomes of interest (Table 1). Thus, they have not been progressive declines in kidney function (inclusion of pa-
able to provide more solid evidence of the risk for ESRD tients with eGFR decline of just >2 mL/min/1.73 m2 in
(as a sole and hard outcome) with longer-term use of RAS the 24 months preceding enrollment), lack of use of a hard
inhibition (eg, over decades). outcome such as ESRD as the primary outcome of interest,
and the potential imbalances in the competing risk for
Continuation Versus Withdrawal of RAS Inhibition mortality that may occur with the 2 alternate strategies.
Among Patients Already Receiving RAS Inhibition While we await results of STOP-ACEi, we highlight some
The majority of the available data derived from clinical of the limited observational data that have investigated the
trials that we have reviewed to date are focused on the role of RAS treatment continuation (vs cessation) in
question of whether RAS blockade should be initiated advanced CKD. One small observational study previously
among patients with advanced CKD. However, there are demonstrated that the rate of eGFR decline was slower
fewer studies that address the question of when and among participants with advanced CKD who had treatment
whether those patients who are already receiving RAS with ACE inhibitors or ARBs withdrawn.27 This study
inhibition should have these agents continued (or suggested that patients with more rapid decline in kidney
discontinued) in the setting of advanced CKD. We believe function during the advanced stages of CKD benefited from
it is prudent to avoid extrapolating evidence from trials RAS inhibitor withdrawal and were observed to experience
and observational studies focused on outcomes after RAS a delay in the need for renal replacement therapy compared
blockade initiation to the management of patients who are with those who continued RAS inhibition.27 In addition, in
already receiving RAS inhibition who have advancing CKD an observational study of 100 patients with advanced CKD,
and hence discuss this issue here separately. patients who were already receiving ACE-inhibitor/ARB
In our anecdotal experience, many providers discon- therapy and had a 25% increase in their serum creatinine
tinue RAS inhibition in the setting of severely reduced levels over baseline values during follow-up who
kidney function (eg, when eGFR declines below 15- discontinued RAS blockade were observed to have im-
20 mL/min/1.73 m2) due to a variety of considerations, provements in kidney function.3,4 This has led some to
including concerns regarding hyperkalemia, expectation of advocate for the discontinuation of RAS inhibition in the
hemodynamic improvements in kidney function with RAS- setting of worsening kidney function with advanced
inhibitor cessation (and therefore gain of additional time CKD among those who are already on RAS inhibition.28,29
for the placement and maturation of dialysis access), and
response to AKI events that may occur during this vulner- Conclusions Regarding RAS Inhibition and Risk for
able period. To date, there is little trial-grade evidence to Renal Outcomes in Advanced CKD
guide this issue. In a small trial of patients with CKD Given the totality of the current evidence in addressing our
(CLcr < 60 mL/min/1.73 m2), an improvement in CLcr controversies question, we suggest that ACE-inhibitor or
from 33 to 43 mL/min/1.73 m2 was observed in those ARB monotherapy initiation appears to be beneficial in
randomly assigned to a 50% reduction in ACE-inhibitor or patients with advanced CKD in the absence of diabetes
ARB dose compared with those with no dose reduction, mellitus, especially among those with proteinuria. How-
although it is unclear how many patients with advanced ever, evidence is more limited among patients with
CKD were included.25 We recommend caution in extrap- advanced CKD and diabetes mellitus given the traditional
olating data from RAS blockade–naive patients with exclusion of many patients with advanced CKD from dia-
advanced CKD to those who have received RAS blockade in betes trials.30 More studies are needed to confirm the
the past and have progressively lost kidney function. benefit of RAS blockade monotherapy initiation in patients
An ongoing randomized controlled trial (STOP-ACEi with diabetes mellitus and advanced CKD (Box 1).
[Multi-Centre Randomised Controlled Trial of ACE inhib- Regarding the risks versus benefits of continuing RAS
itor/ARB Withdrawal in Advanced Renal Disease]) of inhibition in advanced CKD, we suggest that in the setting
stopping (vs continuing) RAS blockade should provide of hypotension or repeated episodes of AKI, cessation of
additional data on the risks and benefits of RAS blockade treatment with these agents seems reasonable. Whether
on kidney disease progression in patients with advanced stopping treatment with these agents routinely in patients
CKD and diabetes mellitus.26 STOP-ACEi will be an open- with advanced CKD who experience rapid declines in
label randomized controlled trial of 410 participants with kidney function will slow the progression to renal
CKD stage 4 or 5 who are currently receiving RAS inhi- replacement therapy is unclear.
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 RAS Inhibition and Risk for Cardiovascular
regimen for 3 years, with the primary outcome being the Mortality in Advanced CKD
difference in kidney function at 3 years. The strengths of Although a number of trials have demonstrated the benefit
this trial include the focus on the advanced CKD of RAS inhibition on cardiovascular (CV) outcomes,31-33

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Box 1. Recommendations for Future Research Among Patients Declines in Kidney Function With Initiation of
With Advanced CKD RAS Inhibition in Advanced CKD
Although ACE inhibitors and ARBs are known to suppress
• Prospective randomized controlled trial testing RAS inhibition
against alternative agents (such as nondihydropyridine cal-
proteinuria, their treatment initiation is also commonly
cium channel blockers) in advanced CKD, especially among associated with increases in serum creatinine levels, which
patients with diabetes for both CV and renal outcomes. are commonly ascribed to hemodynamic changes and
• Studies that inform how to best individualize therapy among thought to be benign.41-44 Traditionally, tolerance of up to
patients with advanced CKD based on heterogeneity in the a 30% increase in serum creatinine level after the initiation
treatment response by factors such as age, race, cause of of ACE-inhibitor or ARB treatment has been recom-
CKD, comorbid conditions. mended.45,46 However, this recommendation was based
• Prospective trials to examine whether hyperkalemia mitiga- primarily on data from trials that excluded patients with
tion will permit use of RAS inhibition in patients with advanced CKD. The prevalence of RAS inhibition use de-
advanced CKD with hard end points such as kidney disease, creases with advancing NDD-CKD stages.47,48 A recent
CV outcomes, or death.
pilot study of combination ACE-inhibitor and ARB use in
• Studies that identify thresholds of concern for adverse renal
outcomes as it relates to acute declines in kidney function adults with advanced CKD demonstrated that almost half
during RAS inhibition initiation or continuation and hyper- could not tolerate dual ACE-inhibitor and ARB therapy due
kalemia, especially in the setting of advanced diabetic kidney to significant declines in kidney function or the onset of
disease. hyperkalemia.49
• Prospective trials of RAS inhibition in advanced CKD among Post hoc analyses of a few randomized controlled trials
patients who are older, are nonproteinuric, or with a history of (AASK, ONTARGET, TRANSCEND [Telmisartan Random-
rapid kidney function decline and acute kidney injury. ized Assessment Study in ACEi Intolerant Subjects With
Abbreviations: CKD, chronic kidney disease; CV, cardiovascular; RAS, renin- Cardiovascular Disease], and RENAAL) have not shown
angiotensin system.
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
few trials have been devoted to the study of RAS inhibition the magnitude of the kidney function decline is greater
and CV outcomes in adults with advanced CKD. The ma- than 15% to 20%.5,50-53 In AASK, these results did not
jority of trials that have assessed the benefit of ACE in- differ by baseline eGFR or level of proteinuria.52 In
hibitors or ARBs on CV outcomes have included a subset of ONTARGET, acute declines in eGFR were associated with a
participants with mild NDD-CKD and tested for effect non–statistically significant tendency toward higher risk
modification by CKD status. Of trials that have shown a for CV outcomes (Table 2).51 However, caution should be
benefit from RAS inhibition,34-36 no effect modification by used in the interpretation of these studies given their post
the presence or absence of NDD-CKD (eGFR < 60 mL/ hoc design and the lack of data regarding long-term ESRD
min/1.73 m2) was noted, although in 2 trials, the benefit risk in the majority of such studies.
of ACE inhibitors tended to be greater among those In an observational study, Schmidt et al54 in the United
with NDD-CKD.36,37 A few trials have failed to show a Kingdom recently demonstrated that declines in eGFR
difference in CV outcomes in patients receiving RAS even as small as 10% within the first 12 months after RAS
inhibition compared to placebo, and results did not differ inhibition are associated with higher risk for adverse
among those with NDD-CKD.18,37,38 However, a major outcomes, including ESRD. However, results of this study
limitation to these studies is the lack of sufficient number should also be interpreted with caution given the longer
of participants with advanced CKD and lack of data for time frame over which these acute declines in eGFR were
proteinuria. assessed. These declines in eGFR may not necessarily be
A number of meta-analyses have focused on the role of related to RAS inhibition, but may reflect CKD progression
RAS inhibition on risk for CV outcomes and shown the and/or selection bias.
benefit of RAS inhibition, especially ACE inhibitors Based on the currently available evidence, it does not
(as compared to ARB therapy).39,40 However, to our appear that eGFR decline after RAS blockade is strongly
knowledge, few studies have examined this question in the associated with risk for adverse renal or CV outcomes
advanced CKD population. based on post hoc secondary analyses of trial-grade data. In
In summary, evidence to address the effect of RAS in- addition, whether concomitant interventions, including
hibition on CV outcomes in patients with advanced CKD is intensive BP lowering with RAS blockade, may predispose
lacking, and as such, there is insufficient data to provide to a higher risk for adverse kidney outcomes has not been
definitive guidance regarding this controversy. Most of the thoroughly investigated. Based on observational and post
data currently available are derived from studies of patients hoc analyses,52,54 we suggest that acute (within 12 weeks
with mild to moderate NDD-CKD, and the inclusion of after initiation of RAS inhibition) declines in eGFR > 20%
patients with more advanced NDD-CKD in future trials of may warrant caution and consideration of cessation of
interventions to assess CV outcomes is needed (Box 1). therapy. However, limitations of the available evidence

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support the need for more clinical trials that directly Advanced CKD Due to Diabetes Mellitus
address our controversies question (Box 1). 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
RAS Inhibition and Risk for Hyperkalemia
with eGFRs ≤ 30 mL/min/1.73 m2 were the RENAAL
Nondiabetic Advanced CKD Study7 and IDNT (Irbesartan Diabetic Nephropathy Trial).8
Several clinical trials provide data to help gauge the risk for Many other clinical trials, including MARVAL (Micro-
hyperkalemia in patients with advanced CKD who do not albumin Reduction with Valsartan), IRMA-2 (Irbesartan in
have diabetes (Table 3). For example, the REIN trial randomly Patients With Type 2 Diabetes and Microalbuminuria), VA
assigned patients with CLcr of 20 to 70 mL/min/1.73 m2 to NEPHRON-D, TRANSCEND, and ONTARGET, excluded
receive ramipril (up to 5 mg daily) versus placebo to achieve patients with eGFRs < 30 mL/min/1.73 m2.15,19,56-63
a goal diastolic BP ≤ 90 mm Hg.12 Among participants with RENAAL Study participants were randomly assigned to
the lowest tertile of kidney function, only 2 in the ramipril receive losartan titrated up to 100 mg daily versus placebo
arm and 1 in the placebo arm were taken off the study in addition to other necessary antihypertensive medica-
medication due to persistent hyperkalemia despite recom- tions to achieve a target BP < 140/90 mm Hg
mended dietary changes, diuretic therapy, and balancing (Table 3).8,64 The lowest baseline eGFR among all
acid-base status. In this lowest tertile of kidney function, participants was 34.4 ± 12.0 mL/min/1.73 m2. Hyper-
potassium levels were significantly higher in the ramipril kalemia resulted in the discontinuation of study medica-
group compared to placebo, but not by more than a mean of tion in 1.1% of patients in the losartan group versus 0.5%
0.5 mmol/L. Similar findings were reproduced in another in the placebo group. Post hoc analysis demonstrated that
trial: even after dose titration of benazepril in patients with 38.4% of patients in the losartan group had serum potas-
advanced CKD, the development of hyperkalemia, defined as sium levels ≥ 5.0 mmol/L at 6 months compared to 22.8%
potassium level ≥ 5.6 mmol/L, was a rare event.6 in the placebo group (P < 0.001); 10.8% in the losartan
In another Chinese trial, 360 hypertensive patients with group and 5.1% in the placebo group had serum potas-
serum creatinine levels between 1.5 and 5.0 mg/dL and sium levels ≥ 5.5 mmol/L. Losartan therapy was associated
mean eGFR of w30 mL/min/1.73 m2 were treated with with significantly higher risk for hyperkalemia at 6
either benazepril or losartan.55 Hyperkalemia, defined as months. Incident hyperkalemia was predictive of a 22%
serum potassium level ≥ 5.6 mmol/L during the pretitra- higher risk for the composite end point of doubling of
tion phase and ≥6 mmol/L during the treatment phase, serum creatinine level or ESRD.65 However, we caution
developed in 8 of 180 patients using benazepril and 8 of that evidence from the RENAAL trial may not be general-
180 patients using losartan, although the number of par- izable to all patients with advanced CKD given the low
ticipants with advanced CKD was not described. Six of these number of enrollees with more advanced disease.8
16 patients had successful optimization of serum potassium In IDNT,7 patients were randomly assigned to receive
levels with diuretics and dietary potassium restriction, and irbesartan, 300 mg, daily versus amlodipine, 10 mg, daily
the other 10 patients withdrew from the study due to versus placebo in addition to other antihypertensive
persistent hyperkalemia. Analysis from an observational medications to target BP < 135/85 mm Hg. The lowest
study that evaluated ACE-inhibitor or ARB therapy in par- eGFR at study enrollment was 15 mL/min/1.73 m2 for
ticipants with advanced CKD found that although such women and 20 mL/min/1.73 m2 for men by both
therapy increased the risk for hyperkalemia, it did not CKD-EPI (CKD Epidemiology Collaboration) and MDRD
translate into increased risk for predialysis mortality.21 (Modification of Diet in Renal Disease) Study
In summary, the evidence addressing the safety aspect equation–based calculations. Eleven of 579 patients using
of our controversies question suggests a definite increase in irbesartan versus 3 of 567 using amlodipine and 2 of 569
risk for hyperkalemia in patients with advanced CKD and patients using placebo (P = 0.01) developed hyperkalemia,
no diabetes mellitus. However, in many of these studies, which led to cessation of the randomized intervention.
despite the increased risk for hyperkalemia with RAS In summary, both the RENAAL Study and IDNT focused
blockade initiation, there was a consistent reduction in on patients with mild to moderate NDD-CKD and demon-
risk for progressive loss of kidney function and incident strated a small but statistically significant risk for developing
ESRD. Thus, the evidence suggests that initiation of RAS hyperkalemia sufficient to stop the ARB monotherapy.
blockade monotherapy may be useful despite the addi- These adverse effects of ARB monotherapy were offset by a
tional safety monitoring that may be required in patients 20% risk reduction of the primary end point of doubling of
with advanced CKD. Hyperkalemia prevention and man- serum creatinine level, ESRD, or death with ARB use.7
agement protocols used in these studies include dietary However, it must be emphasized that these trials included
potassium restriction, correction of acid-base imbalances, patients with diabetes mellitus, a group at higher risk for
avoidance of concomitant use of medications that promote hyperkalemia. Not all patients with diabetes may be at the
hyperkalemia, optimization of diuretic use, and use of same risk for hyperkalemia because subphenotypes, such as
cation-exchange resins when clinically indicated.46 those with type 4 renal tubular acidosis, may be at greater

8 AJKD Vol XX | Iss XX | Month 2018


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
Perspective

risk. More clinical trials are required to directly establish the MD (MRW); University of Hawaii John A. Burns School of
risk-benefit balance of ACE-inhibitor or ARB monotherapy Medicine, Honolulu, HI (JIL); Division of Nephrology, Department
of Medicine, Johns Hopkins University School of Medicine,
in adults with diabetes and advanced CKD. Given the
Baltimore, MD (BJ, MJC); Division of Nephrology, Department of
availability and tolerability of newer potassium-binding Medicine, Wake Forest University School of Medicine, Winston-
agents such as patiromer66,67 and sodium zirconium Salem, NC (MVR); Division of Nephrology and Hypertension,
cyclosilicate,68,69 which have both favorable efficacy and Department of Public Health Sciences and Medicine, Loyola
safety profiles among patients with hyperkalemia receiving University Chicago Stritch School of Medicine, Maywood, IL
(HMK); and Division of Nephrology, Department of Medicine,
RAS inhibition, we believe that hyperkalemia will be less
University of California San Francisco, San Francisco, CA (EK).
likely to limit the initiation or continuation of RAS inhibi-
Address for Correspondence: Matthew R. Weir, MD, Division of
tion among patients with CKD in the future. Nephrology, University of Maryland School of Medicine, 22 S
Greene St, Rm N3W143, Baltimore, MD 21201. E-mail: mweir@
som.umaryland.edu
Conclusions
Support: There was no direct financial support for the preparation of
We have carefully reviewed the available evidence from this article. Dr Ku was supported by National Institutes of Health
clinical trials regarding the use of RAS blockade in patients grant HL 131023. Dr Weir is supported by U01DK116095-01,
with advanced CKD. There is clearly more information R01DK066013, R01HL127422, R01HL132372-01A1, and U01
available with regard to patients with advanced CKD with DK1061022.
versus without diabetes mellitus. Current evidence suggests Financial Disclosure: Dr Weir serves on the Scientific Advisory
that declines in eGFRs or increases in serum potassium Board for Relypsa, Vifor, and Astra Zeneca. The remaining authors
declare that they have no relevant financial interests.
levels after RAS blockade are not associated with higher risk
Other Disclosures: Dr Rocco is Chair of KDOQI. Dr Kramer is
for adverse renal outcomes. However, available clinical trial KDOQI Vice Chair for Controversies and Commentaries and is
data may not be generalizable to patients with advanced President-Elect of the NKF. Dr Choi is President of the NKF.
CKD due to diabetes mellitus. Moreover, individual patients Dr Jaar is the KDOQI Vice Chair for Education.
may respond differently to RAS inhibition. Given these Acknowledgements: We acknowledge the NKF for encouraging
controversies, individualization of treatment plans with the development of this article.
careful assessment of the risk to benefit ratio of RAS inhi- Peer Review: Received December 14, 2017. Evaluated by 3 external
bition should be the principle on which we consider the use peer reviewers, with direct editorial input from an Associate Editor,
of these important medications with regard to their benefits who served as Acting Editor-in-Chief. Accepted in revised form
June 8, 2018. The involvement of an Acting Editor-in-Chief was to
on CKD progression. We encourage providers to consider comply with AJKD’s procedures for potential conflicts of interest
factors such as patient age, degree of proteinuria suppres- for editors, described in the Information for Authors & Journal
sion with RAS initiation, historical and prospective occur- Policies.
rence of AKI, and rate of kidney function decline when
making decisions surrounding the initiation, avoidance,
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12 AJKD Vol XX | Iss XX | Month 2018