CLINICAL RESEARCH www.jasn.

org

Relationship of Kidney Injury Biomarkers with

Long-Term Cardiovascular Outcomes after
Cardiac Surgery
Chirag R. Parikh,*† Jeremy Puthumana,* Michael G. Shlipak,‡ Jay L. Koyner,§
Heather Thiessen-Philbrook,* Eric McArthur,| Kathleen Kerr,¶ Peter Kavsak,**
Richard P. Whitlock,†† Amit X. Garg,‡‡§§| and Steven G. Coca||
*Program of Applied Translational Research, Department of Medicine, Yale University School of Medicine, New
Haven, Connecticut; †Department of Internal Medicine, Veterans Affairs Medical Center, West Haven, Connecticut;
‡
Division of General Internal Medicine, San Francisco Veteran Affairs Medical Center, San Francisco, California;
§
Section of Nephrology, Department of Medicine, University of Chicago, Pritzker School of Medicine, Chicago,
Illinois; |Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; ¶Department of Biostatistics, University
of Washington, Seattle, Washington; **Departments of Pathology and Molecular Medicine and ††Surgery,
McMaster University, Hamilton, Ontario, Canada; ‡‡Division of Nephrology, Department of Medicine, London
Health Sciences Centre, London, Ontario, Canada; §§Institute for Clinical Evaluative Services, Toronto, Ontario,
Canada; ||Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York,
New York

ABSTRACT
Clinical AKI, measured by serum creatinine elevation, is associated with long-term risks of adverse cardiovas-
cular (CV) events and mortality in patients after cardiac surgery. To evaluate the relative contributions of urine
kidney injury biomarkers and plasma cardiac injury biomarkers in adverse events, we conducted a multicenter
prospective cohort study of 968 adults undergoing cardiac surgery. On postoperative days 1–3, we measured
five urine biomarkers of kidney injury (IL-18, NGAL, KIM-1, L-FABP, and albumin) and five plasma biomarkers of
cardiac injury (NT-proBNP, H-FABP, hs-cTnT, cTnI, and CK-MB). The primary outcome was a composite of
long-term CV events or death, which was assessed via national health care databases. During a median
3.8 years of follow-up, 219 (22.6%) patients experienced the primary outcome (136 CV events and 83 addi-
tional deaths). Compared with patients without postsurgical AKI, patients who experienced AKI Network
stage 2 or 3 had an adjusted hazard ratio for the primary composite outcome of 3.52 (95% confidence interval,
2.17 to 5.71). However, none of the five urinary kidney injury biomarkers were significantly associated with the
primary outcome. In contrast, four out of five postoperative cardiac injury biomarkers (NT-proBNP, H-FABP,
hs-cTnT, and cTnI) strongly associated with the primary outcome. Mediation analyses demonstrated that
cardiac biomarkers explained 49% (95% confidence interval, 1% to 97%) of the association between AKI
and the primary outcome. These results suggest that clinical AKI at the time of cardiac surgery is indicative
of concurrent CV stress rather than an independent renal pathway for long-term adverse CV outcomes.

J Am Soc Nephrol 28: 3699–3707, 2017. doi: https://doi.org/10.1681/ASN.2017010055

It is broadly accepted that clinical AKI, defined by an Received January 17, 2017. Accepted July 5, 2017.

acute rise in the concentration of serum creatinine,
is associated with increased risk for cardiovascular
disease (CVD) and mortality.1,2 We have previously
shown that kidney injury confers increased risk for
long-term all-cause mortality among cardiac sur-
gery recipients. In addition, the risk of long-term
Published online ahead of print. Publication date available at
www.jasn.org.
Correspondence: Dr. Chirag R. Parikh, Section of Nephrology,
Yale University School of Medicine, 60 Temple Street, Suite 6C,
New Haven, CT 06510. Email: chirag.parikh@yale.edu
Copyright © 2017 by the American Society of Nephrology

J Am Soc Nephrol 28: 3699–3707, 2017 ISSN : 1046-6673/2812-3699 3699

 CLINICAL RESEARCH www.jasn.org
mortality was seen even in those with “subclinical AKI,” who
are patients without clinical AKI but have high levels of kidney
injury biomarkers.3 Animal studies have suggested that AKI
results in distant organ effects, including cardiac injury4,5;
however, it is unclear whether these processes occur in hu-
mans and directly link AKI to CVD.
The rise in serum creatinine indicating clinical AKI that
occurs after cardiac surgery is either caused by structural kid-
ney damage or hemodynamic derangements that reduce GFR
without significant injury to the kidney. There are novel urine
and plasma biomarkers that can specifically separate these two
distinct processes. Urinary biomarkers such as IL-18, neutro-
phil gelatinase-associated lipocalin (NGAL), kidney injury
molecule 1 (KIM-1), and liver-type fatty acid–binding protein
(L-FABP) are associated with clinical AKI and specifically de-
note acute damage to the tubular cells. Plasma biomarkers
including N-terminal pro-B-type natriuretic peptide (NT-
proBNP), heart-type fatty acid–binding protein (H-FABP),
high-sensitivity cardiac troponin T (hs-cTnT), cardiac tropo-
nin I (cTnI), and creatine kinase MB (CK-MB) are also asso-
ciated with clinical AKI. These instead track cardiac injury
and dysfunction leading to reduced perfusion and hemody-
namic imbalance, which could lead to reduced glomerular
filtration and increase in serum creatinine. It is unknown
which of these two processes, or both, are direct causes of
long-term cardiovascular events.
To explore these concepts, we analyzed data from a pro-
spective cohort study of adults undergoing cardiac surgery
and examined the relationships among serum creatinine–
defined clinical AKI, urinary biomarkers specific for kidney
injury, and plasma biomarkers specific for cardiac function.
We quantified the independent associations of each indi-
vidual biomarker with the long-term composite primary
Figure 1. Flow diagram of patient selection into the study cohort.
3700 Journal of the American Society of Nephrology
outcome of CV events and mortality, as well as with CV
events alone. Additionally, we performed mediation analyses
to assess the contribution of cardiac injury versus kidney
injury on the relationship between clinical AKI and the pri-
mary outcome.
RESULTS
The final analytic cohort included 968 adults who underwent
cardiac surgery between July of 2007 and December of 2009
(Figure 1). Baseline characteristics of patients stratified by se-
rum creatinine–based AKI status are presented in Table 1. The
average age was 73.4 years and 69% were men. Most surgeries
were elective (81%) and used cardiopulmonary bypass (90%).
The mean preoperative eGFR was 66.5 ml/min per 1.73 m2.
Three hundred forty eight (36%) patients developed serum
creatinine–based AKI after surgery. Patients who developed
AKI were more likely to have a history of diabetes, hyperten-
sion, and congestive heart failure. All results exhibited no sex-
based differences.
Postoperative Creatinine-Based AKI and Risk of CV
Events and Mortality
During a median follow-up of 3.8 (3.1–4.6) years, 219 (22.6%)
patients experienced the primary composite outcome of CV
events or death. Of these, 136 (14.1%) experienced a CVevent,
and 83 (8.6%) died without a CV event. Figure 2A shows the
event rates of the primary composite outcome, after patients
were stratified according to AKI stage. AKI Network stages
were independently associated with the primary composite
outcome. Compared with patients without AKI, the adjusted
hazard ratios were 1.99 (95% confidence interval [95% CI],
J Am Soc Nephrol 28: 3699–3707, 2017
 www.jasn.org CLINICAL RESEARCH

Table 1. Baseline characteristics stratified by AKI status in Figure 4A and Supplemental Table 2.
Characteristic AKI (n=348) No AKI (n=620) P Value In unadjusted analyses, urine L-FABP con-
Demographics centration, urinary albumin, and albumin-to-
Age at the time of surgery, yr 73.3 (8.3) 73.5 (8.3) 0.78 creatinine ratio were modestly associated
Male 253 (73%) 417 (67%) 0.08 with the primary composite outcome.
White 330 (95%) 601 (97%) 0.10 However, adjustment for patient and op-
Medical history (time of surgery) erative characteristics attenuated these
Diabetes 147 (42%) 219 (35%) 0.03 relationships, and they were no longer
Hypertension 293 (84%) 479 (77%) 0.01 statistically significant.
Congestive heart failure 108 (31%) 120 (19%) ,0.001
Left ventricular ejection fraction ,40% 35 (10%) 58 (9%) 0.72
Peak Postoperative Plasma
Previous myocardial infarction 89 (26%) 155 (25%) 0.67
Biomarkers and Risk of CV Events and
eGFR, ml/min per 1.73 m2 63.7 (18.6) 68.1 (18.1) ,0.001
eGFR 0.01
Mortality
.60 ml/min per 1.73 m2 209 (60%) 421 (68%) Plasma biomarkers of kidney injury were
30–60 ml/min per 1.73 m2 123 (35%) 186 (30%) associated with AKI in this cohort (Sup-
,30 ml/min per 1.73 m2 16 (5%) 13 (2%) plemental Figure 1). The correlation
Serum creatinine, mg/dl 1.1 (0.9–1.3) 1.0 (0.9–1.2) ,0.001 coefficients between urine and plasma
Cardiac catheterization (72 h preoperative) 54 (9%) 34 (10%) 0.62 biomarkers are shown in Supplemental
STS score 9.5 (3.6) 10.2 (3.9) ,0.01 Table 1. Urine L-FABP and NGAL had
Surgical characteristics weak to moderate correlations with the
Elective surgery 255 (73%) 531 (86%) ,0.001 cardiac biomarkers, whereas the other
Isolated CABG or valve surgery 261 (75%) 494 (80%) 0.19
three urinary biomarkers were not corre-
Off-pump 34 (10%) 63 (10%) 0.83
lated with the cardiac biomarkers. Four
Reoperation 4 (1%) 10 (2%) 0.16
Perfusion time, min 122 (64) 103 (50) ,0.001
of the cardiac injury biomarkers were sig-
Crossclamp time, min 84 (48) 70 (39) ,0.001 nificantly associated with the primary
Number of diseased coronary vessels 0.67 composite outcome in unadjusted and
None 82 (24%) 159 (26%) adjusted analyses (Figure 4B, Supplemental
One 48 (14%) 92 (15%) Table 2). Associations were strongest for
Two 67 (19%) 126 (20%) NT-proBNP, followed by H-FABP, hs-
Three 150 (43%) 239 (39%) cTnT, and cTnI, whereas CK-MB showed
Postoperative complications no significant association.
AKI Network stage
Stage 1 98 (28%) 0 (0%) N/A
Mediation Analyses
Stage 2 or 3 20 (6%) 0 (0%) N/A
We performed mediation analyses to as-
AKI duration
1–2 d 63 (18%) 0 (0%) N/A
sess and compare the presumptive effects
3–6 d 34 (10%) 0 (0%) N/A of cardiac injury versus kidney injury for
$7 d 21 (6%) 0 (0%) N/A attenuating the association between clin-
Ventilator .48 h 32 (9%) 6 (1%) ,0.001 ical AKI and the primary outcome (Table
ICU LOS 2 (1–4) 2 (1–3) ,0.001 2). Approximately half of the association
Hospital LOS 7.0 (6–11) 6.0 (5) ,0.001 between clinical AKI and the primary
Values reported are mean (SD), n (%), or median (interquartile range). Small cell counts are only pre- composite outcome was explained by
sented for data collected by TRIBE-AKI and not from ICES data holdings. LOS, length of stay. the five cardiac pathway biomarkers (49%;
95% CI, 1% to 97%). In contrast, the esti-
1.46 to 2.71) for patients who experienced stage 1 AKI and mated proportion of the effect mediated by the five kidney
3.52 (95% CI, 2.17 to 5.71) for patients who experienced stage injury biomarkers was essentially zero (1%; 95% CI, 218%
2 or 3 AKI (Figure 3A). Additionally, duration of AKI was to 19%).
significantly associated with the primary composite outcome
in a graded manner (Figures 2B and 3B). Sensitivity Analysis for CV Events Alone
We examined the associations of clinical AKI by serum creat-
Peak Postoperative Urine Biomarkers and Risk of CV inine, urinary kidney injury biomarkers, and plasma cardiac
Events and Mortality injury biomarkers with CVevents alone (excluding mortality).
Postoperative urine biomarkers were associated with AKI in The findings paralleled those for the composite outcome, re-
this cohort (Supplemental Figure 1). The unadjusted and vealing strong associations for AKI stage and duration with
adjusted associations of five peak postoperative urine bio- CV events. None of the urinary kidney injury biomarkers had
markers with the primary composite outcome are presented a significant association with CV events, whereas four of the

J Am Soc Nephrol 28: 3699–3707, 2017 AKI and CVD after Cardiac Surgery 3701
 CLINICAL RESEARCH www.jasn.org

Figure 2. Increased Risk for CV events or death by increasing AKI stage or duration of AKI. Differently dashed lines indicate different AKI
stages or duration, as explained in the figure.

3702 Journal of the American Society of Nephrology J Am Soc Nephrol 28: 3699–3707, 2017

Figure 3. AKI stage and duration are independently associated
wtih CV events or death. Adjusted hazard ratios are displayed here
by AKI stage (A) and duration (B). 95% CIs are shown, with vertical
dashed gray lines indicating hazard ratios of 1. n represents the
number of events for each category.
plasma cardiac markers had a significant association with the
CV outcome (Supplemental Table 3).
DISCUSSION
In this established multicenter cohort study of adults under-
going cardiac surgery, we found that severity and duration of
postoperative creatinine-defined AKI were strongly associated
with CV events and mortality; however, peak postoperative
elevations in urinary kidney injury biomarkers were not sig-
nificantly associated with increased risk after adjusting for
confounders. In contrast, peak plasma biomarkers of cardiac
injury were indeed associated with the primary outcome, even
after adjustment for the same confounders. Mediation analyses
estimated that the peak cardiac injury biomarkers explained
approximately half of the association between clinical AKI
and the primary composite outcome of CV events and mor-
tality, whereas the peak kidney injury biomarkers did not con-
tribute to this relationship (Figure 5). Results were virtually
identical when CV events were considered as the sole end
point. These results indicate that intrinsic kidney damage, as
indicated by specific urine biomarkers, does not appear to be
causally related to CV outcomes; rather, our data suggest that
J Am Soc Nephrol 28: 3699–3707, 2017
www.jasn.org CLINICAL RESEARCH
the association between serum creatinine–defined AKI and
CV events is more likely a result of hemodynamic changes or
underlying cardiac injury and dysfunction.
Our findings challenge the prevalent view that AKI itself is
causally linked to CVD. A growing number of clinical studies
have shown that AKI is associated with long-term cardiovas-
cular outcomes after discharge.6–9 Preclinical models have
shown that AKI can initiate a systemic inflammatory response
and activation of the renin-angiotensin system, which may
produce distant organ effects including cardiac cell apoptosis,
leukocyte infiltration, myocardial fibrosis, and ultimately, car-
diac dysfunction.4,5 However, establishing causality in obser-
vational studies is difficult, and some have argued that the
majority of the observed strong associations between clinical
AKI and poor outcomes are caused by residual confound-
ing.10,11 This argument is made on the basis of the fact that
the kidney is an excellent barometer of cardiac and vascular
function. As serum creatinine is currently the routine clinical
marker of kidney function, previous studies have typically
used acute changes in creatinine to define AKI.1 These prior
studies linking AKI with CVD generally used large registries,
and were not able to distinguish the reasons for the change
in serum creatinine (prerenal/hemodynamic versus intrinsic
AKI). Serum creatinine is routinely measured almost daily in
hospitalized patients, and the peak rise in creatinine during a
patient’s hospital stay has been consistently associated with
long-term outcomes. Without further exploration using bio-
markers, acutely impaired kidney health has appeared to be a
causal risk factor for CVD. Thus, it is vitally important to
utilize more biologic data to parse out this relationship in
the clinical arena. Biomarkers of kidney damage are more sen-
sitive for detecting kidney injury and are preferred for pro-
spective analyses. Our study examined the effect of kidney
injury on CVD through the measurement of both serum cre-
atinine and novel biomarkers. Our results indicate that the
associations between serum creatinine–defined AKI and car-
diovascular and mortality risk may not be directly causal, at
least in the setting of cardiac surgery.
Our study has several strengths. It is a large, multicenter
cohort utilizing several key kidney and cardiovascular bio-
markers that were measured from samples collected, stored,
and analyzed under standardized protocols. Our findings were
consistent across multiple biomarkers and remained consistent
after adjustment for multiple covariates, which supports their
validity. However, there are also several limitations of our study
that merit discussion. We only included patients undergoing
cardiac surgery, and thus the relationship between the bio-
markers and outcomes may not generalize to patients with-
out a high burden of baseline CV disease or other AKI-prone
conditions. Second, because our study was observational, we
are not able to draw conclusions about how therapies for kidney
injury may affect CVD. Third, the severe AKI defined here by
serum creatinine and kidney injury biomarkers may have been
less severe than that seen in other cohorts and other settings,
and there were fewer numbers of patients with severe AKI.
AKI and CVD after Cardiac Surgery 3703
 CLINICAL RESEARCH www.jasn.org

by kidney tubular injury. These findings

also suggest that treatments that solely tar-
get kidney injury may not improve subse-
quent cardiovascular prognoses.

CONCISE METHODS

Study Population
The detailed methods of the TRIBE-AKI cohort
have been described previously.12 Between July
of 2007 and December of 2009, we prospec-
tively enrolled 1219 adults undergoing cardiac
surgery (cardiopulmonary bypass grafting or
valve surgery) who were at high risk for AKI at
six academic medical centers in North Amer-
ica. The study was approved by the institu-
tional review board of each participating site,
and written informed consent was obtained
from all participants. Patients who died during
hospitalization (n=20) were excluded from the
analyses.3

Sample Collection and Biomarker

Assays
Sample collection and processing were per-
formed as described previously.12 In brief, we
collected urine and blood samples preopera-
tively and then daily, for up to 5 days after
surgery. The first postoperative sample was col-
lected within 6 hours of the end of surgery. For
the first 24 hours after surgery, urine samples
were collected every 6 hours. The remaining
Figure 4. Peak post-operative plasma biomarkers are independently associated with daily urine and blood samples were obtained
CV events and mortality, while peak post-operative urine biomarkers are not in- at the time of routine morning blood collection.
dependently associated with the outcome. Adjusted hazard ratios are displayed here We stopped sample collection on day 3 in pa-
by log-transformed urine biomarkers (A) and plasma biomarkers (B). 95% CIs are shown, tients who did not experience a significant in-
with vertical dashed gray lines indicating hazard ratios of 1. n represents the number of crease in serum creatinine. Blood samples were
patients.
collected in EDTA tubes, centrifuged to separate
plasma, and subsequently stored at 280°C.
Despite this, even stage 1 AKI was strongly associated with the We measured urinary IL-18, NGAL, KIM-1, L-FABP, and albumin
primary outcome (adjusted hazard ratio of 2.0; 95% CI, 1.5 to as previously described.12–14 In plasma, we measured NT-proBNP,
2.7) and can potentially be used for clinical prediction of future H-FABP, hs-cTnT, cTnI, and CK-MB.15,16 Peak biomarker values
CV disease. Finally, although we adjusted for several potential were defined as the highest observed biomarker value within the first
confounders, our results may have been affected by residual 3 days after surgery.
confounding.
In this study, we have analyzed data from the Translational Study Variables
Research Investigating Biomarker Endpoints for AKI (TRIBE- Using preoperative creatinine as the baseline creatinine, AKI was
AKI) cohort to demonstrate that the increased risk for CV defined as a $50% or 0.3 mg/dl increase in postoperative serum
events and death that is associated with clinically defined creatinine, within 7 days of surgery. Severity of AKI was classified
AKI does not seem to be mediated by biomarkers of kidney by the AKI Network staging criteria on the basis of the peak serum
injury, but rather by biomarkers of cardiac injury. Thus, the creatinine within 7 days of surgery.17 We also evaluated duration of
association of creatinine-defined AKI with cardiovascular risk AKI, which was defined by the number of days AKI was present after
is more likely explained by underlying cardiac damage and surgery, during hospitalization. Duration of AKI was also stratified
subsequent hemodynamic derangement rather than directly into three categories, as published in prior reports.18,19

3704 Journal of the American Society of Nephrology J Am Soc Nephrol 28: 3699–3707, 2017
 www.jasn.org CLINICAL RESEARCH

Table 2. Mediation analysis using univariable Cox held at the Institute for Clinical Evaluative Sciences (ICES). These
proportional hazards models with the primary composite datasets were linked using unique, encoded identifiers and analyzed at
outcome of cardiovascular events and death ICES. We identified patients with CV events using International Classi-
Log-Transformed Proportion of Effect fication of Diseases, 9th and 10th revisions, Ontario Health Insurance
Source
Biomarker Explained (95% CI), % Plan, and Canadian Classification of Health Interventions codes (Sup-
Plasma CK-MB 12 (217 to 41) plemental Table 4).20–28 These codes have been shown to be highly
NT-proBNP 34 (22 to 70) sensitive, with excellent positive predictive value.29–31 Patients who
hs-cTnT 21 (211 to 53) could not be linked were excluded from the analyses (Figure 1).
cTnI 16 (214 to 46)
H-FABP 37 (23 to 77)
All plasma 49 (1 to 97) Statistical Analyses
Urine Albumin 8 (23 to 18) Descriptive statistics were reported as mean (SD) or median
IL-18 23 (219 to 13) (interquartile range) for continuous variables, and as frequency (per-
KIM-1 0 (212 to 13) centage) for categorical variables. Continuous variables were com-
L-FABP 12 (23 to 27) pared with Wilcoxon rank sum tests or Kruskal–Wallis tests, and
NGAL 1 (212 to 14) categorical variables were compared via chi-squared or Fisher exact
All urine 1 (218 to 19) tests as appropriate.
We used Cox regression models to estimate the associations be-
The primary outcome of this study was a composite of CV events tween AKI, urinary kidney biomarkers, and plasma cardiac bio-
and death. We obtained vital status after discharge using several markers with the primary composite outcome. We used Schoenfeld
methods, and crossreferenced when possible. For patients living in residuals to evaluate the proportional hazards assumption. Peak post-
the United States, we called patients’ homes, reviewed hospital re- operative biomarker concentrations from days 1–3 were modeled as
cords, and searched the National Death Index. For Canadian partic- log-transformed (base e) continuous variables. The statistical model
ipants, we called patients’ homes and utilized data from the Institute adjusted for the following variables: Society of Thoracic Surgery
for Clinical Evaluative Sciences. There was complete ascertainment score,32 sex, cardiopulmonary bypass time .120 minutes, nonelec-
of vital status in the cohort. tive surgery, hypertension, congestive heart failure, preoperative
CV events were defined as major adverse cardiovascular events: urine albumin-to-creatinine ratio, and cardiac catheterization in
hospitalization for acute coronary syndrome, myocardial infarction, the 72 hours before surgery. The STS score is a previously published
congestive heart failure, coronary bypass, and percutaneous coronary score to estimate the risk of postoperative dialysis in patients undergo-
intervention. For patients living in the United States, information ing cardiac surgery and is comprised of preoperative serum creatinine,
about CV events was obtained through linkages with Center for age, surgery type, diabetes, chronic lung disease, recent myocardial
Medicare and Medicaid Services (CMS) databases. Variables used in infarction, race, reoperation, New York Heart Association class, and
the probabilistic matching to CMS data included surgery site, surgery cardiogenic shock. Chronic lung disease was not captured in the
date, age, sex, race, admission date, discharge date, death date, and zip TRIBE-AKI Study, thus in calculating the STS score, we assumed
code. For Canadian participants, information was obtained from data that none of the patients had this condition.

Figure 5. Schematic displaying that CVD risk in not significantly associated with urine biomarkers but is significantly associated with plasma
biomarkers. Solid lines represent associations presented in Figure 3 (AKI to composite outcome of CV events and death) and Figure 3
(biomarkers to composite outcome of CV events and death). Dashed lines represent models explored in mediation analyses and reported in
Table 2. CV, cardiovascular; Cr, creatinine.

J Am Soc Nephrol 28: 3699–3707, 2017 AKI and CVD after Cardiac Surgery 3705
 CLINICAL RESEARCH www.jasn.org
Mediation analysis was conducted to investigate the strength of
evidence that the association between clinical AKI and the composite
outcome was a causal effect resulting from direct kidney injury. Using
the SAS MEDIATE macro,33 Cox proportional hazards regression
models were fit for the composite outcome with clinical AKI alone
and with clinical AKI plus each biomarker. The proportion of effect
explained by each biomarker was calculated on the basis of the
change to the AKI regression coefficient after adding the biomarker
to the Cox regression model, and the variance was derived using the
delta method (see Lin et al., Equation 5, page 1519).34 We per-
formed mediation analyses for each biomarker separately and by
sample type (all urine and all plasma), and we used models both
with and without covariate adjustment.
Analyses were conducted using SAS version 9.4 (SAS Institute,
Cary, NC) and R version 3.1.2 (R Foundation for Statistical Comput-
ing, Vienna, Austria). All tests of significance were two-sided, with
P,0.05 considered significant. Small cell counts are only presented
for data collected by the TRIBE-AKI Study, as in order to comply with
privacy regulations at the Institute for Clinical Evaluative Sciences for
minimizing the chance of identification of a study participant, data
numbers of participants are suppressed in the case of five or fewer
participants (reported as five or fewer).
ACKNOWLEDGMENTS
The urine biomarker assays were donated by Abbott Diagnostics (IL-
18 and NGAL) and Sekisui Diagnostics LLC (KIM-1 and L-FABP).
The plasma cardiac biomarkers were provided in kind by Beckman
Coulter, Roche Diagnostics, and Randox Laboratories.
The research reported in this article was supported by the American
Heart Association Clinical Development Award, as well as by the grant
R01HL-085757 from the National Heart, Lung, and Blood Institute.
C.R.P. is supported by a National Institutes of Health (NIH) grant
(K24DK090203). S.G.C., A.X.G., and C.R.P. are also members of the
NIH-sponsored Assess, Serial Evaluation, and Subsequent Sequelae in
AKI Consortium (U01DK082185). The study was also supported by
Clinical and Translational Science Award grant UL1 RR024139 from
the National Center for Research Resources. This study was supported
by the Institute for Clinical Evaluative Sciences (ICES), which is
funded by an annual grant from the Ontario Ministry of Health and
Long-Term Care (MOHLTC). A.X.G. is supported by the Dr. Adam
Linton Chair in Kidney Health Analytics.
The granting agencies, Abbott Diagnostics, Genzyme Diagnostics,
Beckman Coulter, Roche Diagnostics, and Randox Laboratories
did not participate in the protocol development, analysis, and in-
terpretation of the results. The opinions, results, and conclusions
reported in this paper are those of the authors and are independent
from the funding sources. No endorsement by ICES or the Ontario
MOHLTC is intended or should be inferred. Parts of this material
are on the basis of data and information compiled and provided by
Canadian Institute for Health Information. However, the analyses,
conclusions, opinions, and statements expressed herein are those of
the authors, and not necessarily those of Canadian Institute for Health
Information.
3706 Journal of the American Society of Nephrology
DISCLOSURES
None.
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This article contains supplemental material online at http://jasn.asnjournals.
org/lookup/suppl/doi:10.1681/ASN.2017010055/-/DCSupplemental.
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