Patient-Oriented, Translational Research: Research Article

Nephrology
American Journal of

Am J Nephrol 2019;49:359–367 Received: August 3, 2018

Accepted: February 27, 2019
DOI: 10.1159/000499574 Published online: April 2, 2019

Association of Acute Kidney Injury with

Cardiovascular Events and Death in Systolic
Blood Pressure Intervention Trial
Brad P. Dieter a Kenn B. Daratha a, b Sterling M. McPherson a, c, e Robert Short a
       

Radica Z. Alicic a, d Katherine R. Tuttle a, d, f

   

a Providence
Medical Research Center, Providence Health Care, Spokane, WA, USA; b College of Nursing, Washington
 

State University, Spokane, WA, USA; c Elson S. Floyd College of Medicine, Washington State University, Spokane, WA,
 

USA; d Department of Medicine, Psychiatry and Behavioral Sciences, Spokane, WA, USA; e Department of Medicine,
   

Psychiatry and Behavioral Sciences, Spokane, WA, USA; f Division of Nephrology, Kidney Research Institute, Institute
 

of Translational Health Sciences, University of Washington, Spokane, WA, USA

Keywords nine. AKI episodes were identified by serious adverse events

Hypertension · Blood pressure · Anti-hypertensive
treatment · Kidney disease · Survival
Abstract
Rationale and Objective: In the Systolic Blood Pressure In-
tervention Trial, the possible relationships between acute
kidney injury (AKI) and risk of major cardiovascular events
and death are not known. Study Design: Post hoc analysis of
a multicenter, randomized, controlled, open-label clinical
trial. Setting and Participants: Hypertensive adults without
diabetes who were ≥50 years of age with prior cardiovascu-
lar disease, chronic kidney disease (CKD), 10-year Framing-
ham risk score > 15%, or age > 75 years were assigned to a
systolic blood pressure target of <120 mm Hg (intensive) or
<140 mm Hg (standard). Predictor: AKI episodes. Outcomes:
The primary outcome was a composite of myocardial infarc-
tion, acute coronary syndrome, stroke, decompensated
heart failure, or cardiovascular death. The secondary out-
come was death from any cause. Analytical Approach: AKI
was defined using the Kidney Disease: Improving Global
Outcomes modified criteria based solely upon serum creati-
or emergency room visits. Cox proportional hazards models
assessed the risk for the primary and secondary outcomes by
AKI status. Results: Participants were 68 ± 9 years of age, 36%
women (3,332/9,361), and 30% Black race (2,802/9,361), and
17% (1,562/9,361) with cardiovascular disease. Systolic
blood pressure was 140 ± 16 mm Hg at study entry. AKI oc-
curred in 4.4% (204/4,678) and 2.6% (120/4,683) in the inten-
sive and standard treatment groups respectively (p < 0.001).
Those who experienced AKI had higher risk of cardiovascular
events (hazard ratio [HR] 1.52, 95% CI 1.05–2.20, p = 0.026)
and death from any cause (HR 2.33, 95% CI 1.56–3.48, p <
0.001) controlling for age, sex, race, baseline systolic blood
pressure, body mass index, number of antihypertensive
medications, cardiovascular disease and CKD status, hypo-
tensive episodes, and treatment assignment. Limitations:
The study was not prospectively designed to determine re-
lationships between AKI, cardiovascular events, and death.
Conclusions: Among older adults with hypertension at high
cardiovascular risk, intensive treatment of blood pressure in-
dependently increased risk of AKI, which substantially raised
risks of major cardiovascular events and death.
© 2019 S. Karger AG, Basel

© 2019 S. Karger AG, Basel Brad P. Dieter, PhD

Providence Medical Research Center
Providence Health Care
E-Mail karger@karger.com
105 W. 8th Avenue, Suite 6050W, Spokane, WA 99204 (USA)
www.karger.com/ajn E-Mail Brad.dieter @ providence.org
 Introduction
Hypertension is a major public health problem greatly
contributing to disability and deaths. Blood pressure is a
modifiable risk factor for both cardiovascular disease and
chronic kidney disease (CKD) [1, 4, 10, 13]. According to
previously reported observational data, for each 20 mm
Hg increment in systolic blood pressure or 10 mm Hg in-
crement in diastolic blood pressure above 120 mm Hg,
the risk of cardiovascular disease approximately doubles
[12]. Antihypertensive therapy reduces risks of heart fail-
ure, stroke, myocardial infarction, and CKD progression
[1, 6, 7]. While the importance of hypertension control is
clear, the optimal blood pressure target has been unclear
and potential benefits versus risks of different targets are
not well understood.
The Systolic Blood Pressure Intervention Trial
(SPRINT) was designed to determine the effect of intensive
treatment to a systolic blood pressure < 120 mm Hg
­compared to standard treatment to systolic blood pressure
<140 mm Hg [6]. SPRINT was stopped nearly 2 years ear-
ly due to benefits of 25 and 27% relative risk reductions for
major cardiovascular events and deaths from any cause,
respectively. Furthermore, there were no differences be-
tween the treatment groups in prespecified renal out-
comes, including progression to end-stage renal disease.
However, kidney-associated adverse events, particularly
acute kidney injury (AKI), occurred more often with in-
tensive treatment. Rates of AKI by investigator report were
4.1% in the intensively-treated group versus 2.5% in the
standard treatment group over the 3.26-year median dura-
tion of follow-up. In a subsequent analysis, rates of adjudi-
cated AKI were similarly higher in the intensive treatment
group compared to the standard treatment group [17].
Relationships between AKI and risk of major cardio-
vascular events and death have not been determined in
SPRINT. Therefore, the objective of this study was to de-
lineate these relationships.
Methods
Design and Participants
SPRINT was a randomized, controlled, open-label clinical trial
conducted at 102 sites in the United States. Participants were
­enrolled from November 2010 to March 2013 [6]. Main inclu-
sion  criteria included: ≥50 years of age, systolic blood pressure
≥130 mm Hg and <180 mm Hg, high cardiovascular risk defined
by clinical or subclinical cardiovascular disease other than stroke,
CKD with an estimated glomerular filtration rate (eGFR) 20–
60 mL/min/1.73 m2, 10-year Framingham risk score ≥15%, or age
≥75 years. Clinical cardiovascular disease was defined as history of
360 Am J Nephrol 2019;49:359–367
DOI: 10.1159/000499574
one or more of MI, ACS, coronary revascularization, carotid revas-
cularization, PAD with revascularization, > 50% stenosis of coro-
nary/carotid/lower extremity artery; or AAA ≥5 mm. Subclinical
cardiovascular disease was defined as a history of one or more of
coronary artery calcium score ≥400, ABI ≤0.90, or LVH. Main ex-
clusion criteria included prior stroke, urine protein excretion >1 g/
day, diabetes mellitus, symptomatic heart failure, cardiac ejection
fraction <35%, and active alcohol or substance use disorder. For the
present analysis, SPRINT participants who experienced AKI after
the primary outcome were excluded from analyses (n = 45). SPRINT
conformed to the Declaration of Helsinki and was approved by in-
stitutional review boards at each of the study sites. All participants
provided written informed consent to join the study.
Participants were assigned to a systolic blood-pressure target of
either <120 mm Hg (intensive treatment) or <140 mm Hg (stan-
dard treatment). Randomization was stratified according to clini-
cal site. Participants and study personnel were aware of study
group assignments. Investigators adjudicating outcomes were un-
aware of study group assignment [6].
Measurements
Clinical, laboratory, and demographic data were collected at
baseline. In addition, clinical and laboratory data were obtained
every 3 months after the baseline assessment. To obtain self-report-
ed cardiovascular event outcomes, structured interviews were per-
formed every 3 months [6]. Electrocardiograms were also obtained
to assess for cardiovascular events. AKI was assessed at all hospital-
izations and defined using Kidney Disease: Improving Global Out-
comes modified criteria incorporating solely serum creatinine.
Urine output was not consistently recorded in SPRINT. AKI epi-
sodes were identified as serious adverse events and emergency de-
partment visits. The present dataset, provided for the SPRINT data
analysis challenge sponsored by the New England Journal of Medi-
cine, only included investigator-reported, unadjudicated AKI. Hy-
potensive episodes were also only investigator reported.
Outcomes
The primary composite outcome included myocardial infarc-
tion, acute coronary syndrome not resulting in myocardial infarc-
tion, stroke, acute decompensated heart failure, or death from car-
diovascular causes [6]. The secondary outcomes were the individ-
ual components of the primary composite outcome, death from
any cause, and the composite of the primary outcome or death
from any cause.
Statistical Analysis
Data were accessed via the Biological Specimen and Data Re-
pository Information Coordinating Center for the SPRINT data
analysis challenge. Baseline characteristics of the study partici-
pants were reported as mean ± SD for normally distributed vari-
ables, median and interquartile range for non-normally distrib-
uted variables, and frequencies and percentages for categorical
variables. Parametric and nonparametric analysis of variance
models were tested for group comparisons at baseline for normal-
ly and non-normally distributed continuous data respectively.
Categorical variables were assessed with the use of chi-square tests.
Effects of intensive versus standard treatment for blood pres-
sure on AKI were analyzed first. The next analyses examined rela-
tionships of AKI with the primary SPRINT outcome and death
from any cause. For both sets of analyses, Kaplan-Meier survival
Dieter/Daratha/McPherson/Short/Alicic/
Tuttle
curves were constructed for the primary and secondary outcomes
with log-rank tests to assess differences in survival. Unadjusted and
adjusted Cox proportional hazards models were fitted and with in-
clusion of baseline clinical risk factors as co-variates (age, sex, race,
systolic blood pressure, body mass index (BMI), number of antihy-
pertensive medications, clinical cardiovascular disease and CKD
status). For associations of AKI with the primary outcome and
death from any cause, models were adjusted for study treatment
assignment. The adjusted models were further adjusted for hypo-
tensive episodes. Internal validation was conducted by split-file
analysis. Mediation analyses were also utilized to evaluate the pro-
portion of the total effect on the primary outcome and death from
any cause associated with AKI. Accelerated failure time models
with Weibull distributions for time to the outcomes were used and
logistic regression was utilized for AKI as the mediator [21]. Mod-
els used for mediation analysis were also estimated and included
baseline clinical risk factors as co-variates (age, sex, race, systolic
blood pressure, BMI, number of antihypertensive medications,
clinical cardiovascular disease and CKD status). An alpha level of
<0.05 was used as the threshold for statistical significance. R statis-
tical computing software (version 3.1.2) was used for all analyses.
Results
Clinical Characteristics
Participants were 68 ± 9 years of age, 36% women
(3,320/9,316), and 30% Black race (2,786/9,316) with a sys-
tolic blood pressure of 140 ± 16 mm Hg at study entry. Base-
line clinical characteristics of participants in the intensive
and standard treatment groups were well-matched overall
[6]. Clinical cardiovascular disease and CKD were present
in 16.7% (1,548/9,361) and 28% (2,615/9,361), respectively,
at baseline. AKI occurred in 3.9% (180/4,654) and 2.1%
(99/4,662) in the intensive and standard treatment groups
respectively (p < 0.001). AKI represented 7.9% of all serious
adverse events reported (274/3,485). Stratification of base-
line characteristics by presence or absence of an AKI epi-
sode showed that participants who experienced AKI were
older, had higher rates of clinical cardiovascular disease,
and CKD, lower eGFR, and were more often taking antihy-
pertensive medications at baseline (Table 1).
Risks of AKI and Kidney Outcomes by
Treatment Groups
Participants receiving intensive treatment had in-
creased risk of AKI compared to standard treatment in the
unadjusted model (hazard ratio [HR] 1.83; 95% CI 1.43–
2.33, p < 0.001; Table 2). Hypotensive episodes occurred
in 3.3% (154/4,654) and 2.0% (91/4,662) of participants in
the intensive and standard treatment groups respectively.
Unadjusted risk of hypotensive episodes was increased in
the intensive treatment group compared to that of the
AKI, Cardiovascular Events and Death in
SPRINT
standard treatment group (HR 1.7; 95% CI 1.32–2.21, p <
0.001). Risk of AKI was not attenuated with control for
covariates consisting of clinical risk factors (age, sex, race,
systolic blood pressure, BMI, number of antihypertensive
medications, and clinical cardiovascular disease and CKD
status), treatment assignment, and hypotensive episodes
(HR 1.80; 95% CI 1.40–2.33, p < 0.001).
Decline in kidney function as measured by eGFR was
greater in the intensive arm compared to the standard
treatment arm. Of the 6,663 participants with available
data, a > 30% reduction in eGFR occurred in 4.0%
(127/3,323) and 1.1% (37/3,340) participants in the inten-
sive and standard treatment groups respectively. Partici-
pants receiving intensive anti-hypertensive treatment
had increased risk of a > 30% reduction in eGFR com-
pared to standard treatment in the unadjusted model (HR
3.59; 95% CI 2.48–5.20, p < 0.001). This risk persisted in
the model fully adjusted for clinical risk factors (age, sex,
race, systolic blood pressure, BMI, number of antihyper-
tensive medications, and clinical cardiovascular disease
and CKD status; HR 3.69; 95% CI 2.54–5.36, p < 0.001).
When hypotensive episodes were added to the adjusted
model, the higher risk of intensive therapy for experienc-
ing a 30% decline in eGFR remained higher (HR 3.70;
95% CI 2.54–5.37, p < 0.001).
Risks of the Primary Outcome and Death Associated
with AKI
Study participants who experienced AKI had higher
risk of the primary cardiovascular outcome (myocardial
infarction, acute coronary syndrome, stroke, acute de-
compensated heart failure, or death from cardiovascular
causes) and death from any cause (Fig. 1a, b). The prima-
ry cardiovascular outcome occurred in 7.3% (39/531) of
participants who experienced AKI versus 2.7% (240/8,545)
of those without AKI (p < 0.001). Death from any cause
occurred in 9.8% (34/347) of participants with AKI versus
2.7% (245/8,969) in those without AKI (p < 0.001). Par-
ticipants who experienced AKI had a significantly higher
risk of the primary cardiovascular outcome (HR 2.38; 95%
CI 1.7–3.32, p < 0.001) and death from any cause (HR 3.43;
95% CI 2.38–4.94, p < 0.001). In fully adjusted models
(age, sex, race, systolic blood pressure, BMI, number of
antihypertensive medications, and clinical cardiovascular
disease and CKD status), including baseline clinical car-
diovascular disease and CKD status, treatment assign-
ment, and hypotensive episodes, AKI significantly in-
creased risks for the primary outcome (HR 1.52; 95% CI
1.05–2.22, p = 0.026) and for death from any cause (HR
2.33; 95% CI 1.56–3.48, p < 0. 001), although the magni-
Am J Nephrol 2019;49:359–367 361
DOI: 10.1159/000499574
Table 1. Baseline characteristics of study participants

Characteristic Intensive treatment Standard treatment

AKI number AKI p value AKI number AKI p value
(n = 180) (n = 4,474) (n = 99) (n = 4,563)

Criterion for increased

cardiovascular risk, n (%)
Age >75 years 61 (33.9) 1,099 (24.6) 0.006 41 (41.4) 1,130 (24.8) <0.001
CKD 102 (56.7) 1,213 (27.1) <0.001 35 (35.4) 1,236 (27.1) <0.001
Cardiovascular disease  
Clinical 45 (25.0) 726 (16.2) 0.002 30 (30.3) 747 (16.4) <0.001
Subclinical 11 (6.1) 234 (5.2) 0.73 5 (5.1) 241 (5.3) 0.99
Women, n (%) 48 (26.7) 1,630 (56.5) 0.009 25 (25.3) 1,617 (35.4) 0.046
Age, years 70.5±10.6 67.8±9.3 <0.001 70.9±10.2 67.9±9.4 0.003
Statin use, n (%)† 82 (45.6) 1,885 (42.4) 0.45 50 (50.5) 2,015 (44.6) 0.28
Race/ethnicity, n (%)    
Hispanic 9 (5.0) 492 (11.0) 0.002 6 (6.1) 474 (10.4) 0.29
Non-hispanic black 72 (40.0) 1,299 (29.0) 34 (34.3) 1,381 (30.3)
Non-hispanic white 98 (54.4) 2,586 (57.8) 59 (59.6) 2,631 (57.7)
Other 1 (0.6) 97 (2.2) 0 (0.0) 77 (1.7)
BMI, kg/m2‡ 29.8±5.9 29.9±5.8 0.72 29.7±6.4 29.8±5.7 0.83
Baseline blood pressure, mm Hg
Systolic 141.0 (16.1) 139.6 (15.7) 0.19 141.7 (16.2) 139.6 (15.4) 0.24
Diastolic 76.0 (12.4) 78.3 (11.8) 0.015 76.7 (13.4) 78.0 (12.0) 0.29
Estimated GFR, mL/min/1.73 m2 58.7±23.8 72.4±20.3 <0.001 55.9±20.3 72.4±20.4 <0.001
Smoking status, n (%)
Never smoked 70 (38.9) 1,974 (44.1) 0.37 25 (25.2) 2,039 (44.7) <0.001
Former smoked 83 (46.1) 1,884 (42.1) 58 (58.6) 1,928 (44.3)
Current smoker 27 (15) 604 (13.5) 16 (16.2) 582 (12.8)
Missing data 0 (0.0) 12 (0.3) 0 (0.0) 14 (0.3)
Number of antihypertensive
medications, n (%)
0 11 (6.1) 419 (9.4) 0.023 5 (2.5) 445 (9.6) <0.001
1 45 (25.0) 1,319 (29.5) 18 (18.2) 1,367 (30.0)
2 59 (32.8) 1,596 (35.7) 33 (33.3) 1,590 (34.8)
3 50 (27.8) 897 (19.9) 35 (35.4) 916 (20.1)
4+ 15 (8.3) 243 (5.4) 8 (8.1) 245 (5.4)
Number of antihypertensive
medications 2.1±1.1 1.8±1.0 0.002 2.23±1.0 1.8±1.0 <0.001

Plus-minus values are means ± SD.

† Due
to some missing data, the total sample size available for the intensive and standard treatment arms were 4,621 and 4,619 for
the statin data respectively.
‡ Due to some missing data, the total sample size available for the intensive and standard treatment arms were 4,622 and 4,617 for

the BMI data respectively.

Clinical cardiovascular disease was defined as history of one or more of MI, ACS, coronary revascularization, carotid revasculariza-
tion, PAD with revascularization, >50% stenosis of coronary/carotid/lower extremity artery; or AAA ≥5 mm.
Subclinical cardiovascular disease was defined as history of one or more of coronary artery calcium score ≥400, ABI ≤0.90, or LVH.
AKI, acute kidney injury; CKD, chronic kidney disease; GFR, glomerular filtration rate; BMI, Body mass index.

tude of risk was attenuated (Table 3). Risk estimates were
similar when the models were adjusted for eGFR as a con-
tinuous variable rather than CKD status (online suppl.
Table 1, see www.karger.com/doi/10.1159/000499574).
There was no significant interaction between AKI events
and treatment assignment on the primary outcome (HR
0.87; 95% CI 0.68–1.12, p = 0.28) or death from any cause
(HR 1.09; 95% CI 0.55–2.15, p = 0.80). When death from
any cause was examined as a competing risk for the pri-
mary outcome, AKI remained significantly associated

362 Am J Nephrol 2019;49:359–367 Dieter/Daratha/McPherson/Short/Alicic/

DOI: 10.1159/000499574 Tuttle
Table 2. Associations of intensive blood pressure treatment with AKI

Variable HR Lower 95% CI Higher 95% CI p value

Model 1
Intensive therapy 1.83 1.43 2.33 <0.001
Model 2
Intensive therapy 1.90 1.49 2.44 <0.001
Age, years 1.02 1.01 1.04 0.007
Gender, women 0.52 0.39 0.70 <0.001
Race/ethnicity
Hispanic 0.67 0.37 1.24 0.21
Other 0.13 0.02 0.96 0.46
Non-hispanic white 0.50 0.37 0.68 <0.001
BMI, kg/m2 1.00 0.98 1.02 0.85
Systolic blood pressure (10 mm Hg) 1.14 1.06 1.23 <0.001
CKD status 3.32 2.54 4.32 <0.001
Cardiovascular disease at baseline 1.54 1.16 2.05 0.003
Number of antihypertensive medications 1.15 1.02 1.3 0.025
Model 3
Intensive therapy 1.80 1.40 2.33 <0.001
Age, years 1.02 1.00 1.03 0.022
Gender, women 0.53 0.38 0.72 <0.001
Race/ethnicity
Hispanic 0.79 0.43 1.47 0.46
Other 0.16 0.02 1.16 0.07
Non-hispanic white 0.46 0.34 0.63 <0.001
BMI, kg/m2 1.01 0.98 1.03 0.63
Systolic blood pressure (10 mm Hg) 1.13 1.05 1.23 0.001
CKD status 3.10 2.36 4.06 <0.001
Cardiovascular disease at baseline 1.47 1.1 1.96 0.008
Number of antihypertensive medications 1.13 0.99 1.28 0.054
Hypotensive event 13.04 9.56 17.77 <0.001

CKD, chronic kidney disease; BMI, body mass index; AKI, acute kidney injury; HR, hazard ratio.

No AKI event
1.00 No AKI event 1.00
Survival probability, %

Survival probability, %

AKI event
0.75 AKI event 0.75

0.50 0.50

0.25 0.25

0 0
0 1 2 3 4 0 1 2 3 4
Time, years Time, years
Number at risk
No AKI event 9,037 8,582 8,216 5,582 1,453 9,037 8,731 8,477 5,836 1,539
a AKI event 324 298 268 167 51 b 324 317 297 198 63

Fig. 1. Survival without the primary outcome (a) or death (b) in participants with and without AKI. Kaplan-Meier curves for the com-
posite primary outcome (myocardial infarction, acute coronary syndrome, stroke, heart failure, or death from cardiovascular causes)
and for death from any cause. AKI, acute kidney injury.

AKI, Cardiovascular Events and Death in Am J Nephrol 2019;49:359–367 363

SPRINT DOI: 10.1159/000499574
Table 3. Associations of AKI with the primary outcome and death from any cause

Variable Primary outcome Death from any cause

HR lower higher p value HR lower higher p value
95% CI 95% CI 95% CI 95% CI

Model 1
AKI 2.38 1.70 3.32 <0.0001 3.43 2.38 4.94 <0.0001
Model 2
AKI 1.73 1.23 2.43 0.002 2.31 1.58 3.39 <0.0001
Age, years 1.04 1.03 1.05 <0.0001 1.06 1.05 1.08 <0.0001
Gender, women 0.77 0.62 0.95 0.013 0.61 0.47 0.79 0.0002
Race/ethnicity
Hispanic 0.86 0.52 1.43 0.56 0.87 0.5 1.51 0.62
Other 1.00 0.48 2.1 0.98 0.51 0.16 1.65 0.26
Non-hispanic white 1.11 0.87 1.43 0.39 0.84 0.63 1.14 0.27
BMI, kg/m2 1.01 0.99 1.03 0.27 0.99 0.97 1.01 0.24
Systolic blood pressure (10 mm Hg) 1.00 1.00 1.01 0.09 1.01 0.99 1.01 0.10
CKD status 1.24 1.03 1.51 0.026 1.31 1.04 1.67 0.024
Cardiovascular disease at baseline 2.19 1.80 2.66 <0.0001 1.62 1.26 2.08 0.0002
Number of antihypertensive medications 1.13 1.03 1.23 0.01 1.04 0.93 1.17
Model 3
AKI 1.52 1.05 2.2 0.026 2.33 1.56 3.48 <0.0001
Age, years 1.04 1.03 1.05 <0.0001 1.06 1.05 1.08 <0.0001
Gender, women 0.78 0.63 0.96 0.019 0.61 0.47 0.79 0.0002
Race/ethnicity
Hispanic 0.87 0.52 1.44 0.59 0.87 0.5 1.51 0.62
Other 1.02 0.49 2.12 0.96 0.51 0.16 1.65 0.26
Non-hispanic white 1.1 0.86 1.42 1.42 0.84 0.63 1.14 0.27
BMI, kg/m2 1.01 0.99 1.03 0.23 0.98 0.97 1.01 0.24
Systolic blood pressure (10 mm Hg) 1.01 1.00 1.01 0.08 1.01 0.99 1.01 0.10
CKD status 1.24 1.03 1.51 0.026 1.32 1.04 1.67 0.024
Cardiovascular disease at baseline 2.18 1.79 2.65 <0.0001 1.62 1.26 2.08 0.0002
Number of antihypertensive medications 1.13 1.03 1.23 0.01 1.04 0.93 1.16 0.46
Hypotensive episode 1.61 1.03 2.53 0.037 0.96 0.52 1.78 0.89

Goodness of fit measures for primary outcome.

Model 1: AIC = 4,763; likelihood ratio test = 32, p < 0.0001.
Model 2: AIC = 4,587; likelihood ratio test = 211, p < 0.0001.
Model 3: AIC = 4,585; likelihood ratio test = 215, p < 0.0001.
Goodness of fit measures for all cause mortality.
Model 1: AIC = 3,035; likelihood ratio test = 42, p < 0.0001.
Model 2: AIC = 2,888; likelihood ratio test = 185 p < 0.0001.
Model 3: AIC = 2,890; likelihood ratio test = 185, p < 0.0001.
AKI, acute kidney injury; BMI, body mass index; CKD, chronic kidney disease.

with an increased risk of the primary outcome (HR 2.50;
95% CI 1.82–3.45, p < 0.001)
Internal validation using split-file analyses demon-
strated high congruency between the derivation (HR
1.77, 95% CI 1.10–2.85, p = 0.019) and validation (HR
2.93, 95% CI 1.95–4.41, p < 0.001) datasets for the effect
of AKI on the primary cardiovascular outcome in fully
adjusted models (age, sex, race, systolic blood pressure,
BMI, number of antihypertensive medications, and clini-
cal cardiovascular disease and CKD status). Internal vali-
dation using split-file analyses also demonstrated high
congruency between the derivation (HR 3.46, 95% CI
2.24–5.35, p < 0.001) and validation (HR 2.71, 95% CI
1.66–4.42, p < 0.001) datasets for the effect of AKI on the
death from any cause in the fully adjusted model. Media-
tion analysis demonstrated the proportion of the primary
outcome mediated by AKI was 86% in the intensive treat-
ment group and 62% in the standard treatment group

364 Am J Nephrol 2019;49:359–367 Dieter/Daratha/McPherson/Short/Alicic/

DOI: 10.1159/000499574 Tuttle
 AKI AKI

Pathway A Pathway A
86% 62%

Intensive Primary Standard Primary

treatment Pathway B outcome treatment Pathway B outcome
14% 38%
a

AKI AKI

Pathway A Pathway A
89% 69%

Death Death
Intensive Standard
from any from any
treatment Pathway B treatment Pathway B
cause cause
11% 31%
b

Fig. 2. Mediation analyses of the association between intensive ver- sents the pathway not mediated by AKI for the composite primary
sus standard blood pressure treatment and the primary outcome outcome (myocardial infarction, acute coronary syndrome, stroke,
and death from any cause with AKI as the mediator. Pathway (a) heart failure, or death from cardiovascular causes; panel a) and for
represents the pathway mediated by AKI and pathway (b) repre- death from any cause (panel b). AKI, acute kidney injury.

(p < 0.001; Fig. 2a). The proportion of the death from any
cause outcome mediated by AKI was 89% in the intensive
treatment group and 69% in the standard treatment
group (p < 0.001; Fig. 2b).
Discussion
Intensive blood pressure treatment increased the risk
of AKI in older adults with hypertension in SPRINT. The
present analyses indicate that AKI risk was independent
of other clinical risk factors including CKD, cardiovascu-
lar disease, episodes of hypotension, and treatment as-
signment. Notably, SPRINT participants with AKI had a
50% higher risk of major cardiovascular events and a two-
fold higher risk of death, which was also independent of
these covariates.
A target systolic blood pressure of <120 vs. <140 mm
Hg produced more adverse events for kidney disease, in-
cluding AKI and 30% eGFR decline, and did not prevent
loss of kidney function over time [6]. Higher risk of AKI
due to intensive blood pressure treatment was similarly el-
evated when analyzed by adjudicated events [7]. The pres-
ent study builds upon prior findings by demonstrating that
increased risk of AKI with intensive treatment was inde-
pendent of hypotension and other clinical risk factors. Fur-
thermore, there was an increased risk of a 30% decline in
eGFR among those in the intensive arm. However, it is
possible that a lower blood pressure target may have a dif-
ferent effect on outcomes over time in patients similar to
SPRINT participants, who had a low prevalence of protein-
uria. Additionally, in patients without CKD, a dose-re-
sponse relationship was observed in which a greater reduc-
tion in mean arterial pressure associated with greater eGFR
decline, and the balance between cardiovascular benefits
and kidney risks were less favorable with larger blood pres-
sure reductions [14]. A systematic review of 9 clinical trials
conducted in participants with non-diabetic CKD demon-
strated that compared to standard treatment, intensive
blood pressure treatment did not reduce rates of overall

AKI, Cardiovascular Events and Death in Am J Nephrol 2019;49:359–367 365

SPRINT DOI: 10.1159/000499574
eGFR decline, reaching 50% eGFR decline, or serum cre-
atinine doubling [20]. In the Action to Control Cardiovas-
cular Risk in Diabetes trial of patients with type 2 diabetes
randomized to a target systolic blood pressure of <120 ver-
sus <140 mm Hg, eGFR was lower and risk of reaching
eGFR <30 mL/min/1.73 m2 was higher without benefit on
cardiovascular outcomes. Taken together, this compila-
tion of data indicates that, for kidney disease, intensive
blood pressure treatment may not provide benefit and in-
creases the risk of adverse events.
In the present SPRINT analyses, episodes of AKI in-
creased risks of major cardiovascular events and death
from any cause. The mediation analysis showed that the
proportional influence of intensive blood pressure treat-
ment on both the primary and death outcomes was 85–
90% for AKI, indicating that the cardiovascular and sur-
vival benefits of intensive blood pressure treatment could
be abrogated by AKI. The increased risk of cardiovascular
events related to AKI stands out as an important observa-
tion, even though the majority of AKI events were consid-
ered mild and most resolved in SPRINT [17]. Similar ob-
servations have been reported in several other studies and
meta-analyses. A recent study reported a strong associa-
tion between AKI and subsequent cardiovascular events
with an 86% increased risk of cardiovascular death [15].
Another showed that compared to no AKI, stage 1 AKI
following coronary angiography increased the risk of
death twofold, while stage 2 or 3 AKI increased the risk of
death approximately fourfold [9]. Several other studies
have demonstrated that patients who experience AKI after
major surgical procedures have higher risks of myocar-
dial infarction, heart failure, stroke, and death from any
cause [2, 3, 7, 8]. A meta-analysis of 47 studies, including
242,388 individuals demonstrated that AKI increased risk
of mortality four-fold and stroke 2-fold [16]. Since AKI
may increase volume retention, these episodes could ex-
acerbate heart failure and myocardial ischemia [18]. AKI
may also activate the sympathetic nervous system via isch-
emia in the kidney as a potential mechanism to increase
risks of cardiovascular events and death [5, 11, 19].
The present analyses have several limitations. First,
SPRINT was not prospectively designed to determine the
effect of AKI on risks of cardiovascular events and death
from any cause. As such, this analysis must be interpreted
as exploratory and hypothesis generating. Second, access
to adjudicated AKI event data was not available for these
analyses. The modified Kidney Disease: Improving Glob-
al Outcomes criteria were used, which incorporates se-
rum creatinine because urine output was not consistently
measured. However, it is possible that some AKI events
366 Am J Nephrol 2019;49:359–367
DOI: 10.1159/000499574
were not captured and AKI events were reported as sin-
gular events, which would underestimate the effect of
AKI on the primary outcome. Hypotension was investi-
gator reported, and as such the effect of hypotension may
be underestimated in the present analysis. In the present
analyses, intensive blood pressure lowering led to a high-
er risk of a 30% reduction in eGFR. However, it is possible
that a blood pressure lower target could lead to benefits
on kidney outcomes over time despite few SPRINT par-
ticipants with proteinuria. These analyses focused on the
relationship of AKI to cardiovascular events and death
from any cause. Although the absolute rate of investiga-
tor-reported AKI was small, among these patients height-
ened vigilance for adverse outcomes, including cardio-
vascular disease, is warranted. Finally, we cannot exclude
the possibility of reverse causality such that cardiovascu-
lar disease may contribute to occurrence of AKI.
In conclusion, among older adults with hypertension
at high cardiovascular risk, targeting an intensive treat-
ment goal of a systolic blood pressure <120 mm Hg inde-
pendently increased risk of AKI, which meaningfully
raised risks of major cardiovascular events and death. The
present study highlights the need to balance the trade-off
of reducing cardiovascular risk through intensive blood
pressure treatment with increased risk of AKI and subse-
quent cardiovascular events.
Acknowledgments
SPRINT was sponsored by the National Heart, Lung, and Blood
Institute along with co-sponsorship by the National Institute of
Diabetes and Digestive and Kidney Diseases, the National Institute
of Neurological Diseases and Stroke, and the National Institute on
Aging. We would like to thank Dr. Allison Lambert, Celestina Bar-
bosa-Leiker, and Cami Jones for their insightful comments on the
manuscript and data analyses.
Financial Disclosure
K.R.T. has received consulting fees regarding therapies for dia-
betic kidney disease from Eli Lilly and Company, Boehringer In-
gelheim, Astra Zeneca, and Gilead Sciences.
Funding Source
K.R.T. is supported by the following National Institutes of
Health grants: National Center for Advancing Translational Sci-
ences UL1 TR00043; National Institute of Diabetes, Digestive, and
Kidney Diseases 1U2CDK114886-01, 5UM1DK100846-02,
1UC4DK101108-01, 1 U54 DK08 3912, U01 DK085689, R34
DK094016.
Dieter/Daratha/McPherson/Short/Alicic/
Tuttle
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