Download Pre-Procedural Glucose Levels and the Risk for Contrast

Journal of the American College of Cardiology
© 2010 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 55, No. 14, 2010
ISSN 0735-1097/10/$36.00
doi:10.1016/j.jacc.2009.09.072
Pre-Procedural Glucose Levels and the
Risk for Contrast-Induced Acute Kidney Injury
in Patients Undergoing Coronary Angiography
Joshua M. Stolker, MD,*† Peter A. McCullough, MD, MPH,‡ Seshu Rao, MD,*†
Silvio E. Inzucchi, MD,§ John A. Spertus, MD, MPH,*† Thomas M. Maddox, MD, MSC,储
Frederick A. Masoudi, MD, MSPH,¶ Lan Xiao, PHD,* Mikhail Kosiborod, MD*†
Kansas City, Missouri; Royal Oak, Michigan; New Haven, Connecticut; and Denver, Colorado
Objectives
We sought to evaluate whether pre-procedural glucose levels are associated with contrast-induced acute kidney
injury (CI-AKI) after coronary angiography.
Background
Although diabetes is a known risk factor for CI-AKI in patients undergoing coronary angiography, whether elevated preprocedural glucose levels (regardless of pre-existing diabetes) are associated with higher risk for CI-AKI is unknown.
Methods
We evaluated 6,358 patients with acute myocardial infarctions undergoing coronary angiography. Patients were stratified
into 5 pre-procedural glucose groups: ⬍110 mg/dl, 110 to ⬍140 mg/dl, 140 to ⬍170 mg/dl, 170 to ⬍200 mg/dl, and
ⱖ200 mg/dl. Logistic regression models were used to evaluate the relationship between glucose levels and risk for CI-AKI,
first in the entire cohort and then in patients with and without established diabetes. The primary outcome was CI-AKI (ⱖ0.3
mg/dl absolute or ⱖ50% relative serum creatinine increase during 48 h after the procedure).
Results
The relationship between pre-procedural glucose and CI-AKI varied markedly in patients with and without diabetes. There was a strong association between glucose and CI-AKI risk in patients without diabetes (CI-AKI rates
across the 5 glucose groups from lowest to highest: 8.2%, 9.9%, 12.4%, 14.9%, and 24.3%; p ⬍ 0.001), but not
in patients with diabetes (20.9%, 16.1%, 16.3%, 14.8%, and 19.2%, respectively; p ⫽ 0.24; p for glucose ⫻ diabetes interaction ⬍0.001). After adjusting for confounders (including baseline glomerular filtration rate), the relationship between higher glucose and greater CI-AKI risk persisted in patients without diabetes (odds ratios
[95% confidence intervals] for glucose groups of 110 to ⬍140 mg/dl, 140 to ⬍170, mg/dl 170 to ⬍200 mg/dl,
and ⱖ200 mg/dl: 1.31 [1.00 to 1.71], 1.51 [1.11 to 2.10], 1.58 [1.03 to 2.43], and 2.14 [1.46 to 3.14] vs. glucose ⬍110 mg/dl, respectively), but this relationship was not seen in patients with established diabetes.
Conclusions
Elevated pre-procedural glucose is associated with greater risk for CI-AKI in patients without known diabetes
who undergo coronary angiography in the setting of acute myocardial infarction. Measures used to prevent CIAKI should be considered in these patients. (J Am Coll Cardiol 2010;55:1433–40) © 2010 by the American
College of Cardiology Foundation
Contrast-induced acute kidney injury (CI-AKI) is a complication of coronary angiography that occurs commonly in
the setting of acute myocardial infarction (AMI) (1,2) and is
associated with severe adverse events, including permanent
renal impairment (2– 4), higher in-hospital and long-term
mortality (2,5–10), recurrent ischemic events (10,11), increased length of stay (2,12), and higher costs (13). Pro-
From the *Mid America Heart Institute of Saint Luke’s Hospital, Kansas City,
Missouri; †University of Missouri–Kansas City, Kansas City, Missouri; ‡William
Beaumont Hospital, Royal Oak, Michigan; §Yale University and Yale-New Haven
Hospital, New Haven, Connecticut; 储Denver VA Medical Center and University of
Colorado Denver, Denver, Colorado; and the ¶Denver Health Medical Center and
University of Colorado at Denver and Health Sciences Center, Denver, Colorado.
The research for this analysis was supported by the American Heart Association Career
Development Award in Implementation Research, awarded to Dr. Kosiborod. Dr. Stolker has
received speaking honoraria from AstraZeneca Pharmaceuticals and Pfizer Pharmaceuticals;
has served as a consultant to Novo Nordisk; and has served on the advisory board of
Educational Testing Consultants, LLC. Dr. Inzucchi has received research grant support from
Eli Lilly. Dr. Spertus has received research grant support from Sanofi-Aventis and Eli Lilly.
Dr. Masoudi was previously a member of the advisory board of Takeda Pharmaceuticals. Dr.
Kosiborod has served on the advisory board of Sanofi-Aventis and has received speaking
honoraria from the Vascular Biology Working Group and DiaVed, Inc. The Cerner
Corporation collected deidentified clinical information for the Health Facts database. The
Cerner Corporation had no role in study design, data analysis, interpretation of findings, or
writing of the manuscript. The American Heart Association had no role in the study.
Manuscript received July 20, 2009; revised manuscript received September 9, 2009,
accepted September 28, 2009.
See page 1441
1434
Stolker et al.
Glucose and Contrast-Induced Acute Kidney Injury
posed pathophysiologic mechanisms through which contrast administration may potentiate renal
AMI ⴝ acute myocardial
injury include oxidative stress, free
infarction
radical damage, and endothelial
CABG ⴝ coronary artery
dysfunction (3,14,15). All of these
bypass grafting
processes also are activated in the
CI-AKI ⴝ contrast-induced
setting of hyperglycemia (3,16),
acute kidney injury
which is common in patients with
GFR ⴝ glomerular filtration
rate
AMIs (17) and has adverse prognostic implications (16,18 –20),
PCI ⴝ percutaneous
coronary intervention
particularly among those who do
not have established diabetes
(19 –21). Thus, it is possible that a
combination of pre-procedural hyperglycemia and contrast
exposure during coronary angiography could significantly increase the risk for CI-AKI.
However, while diabetes is a well-recognized risk factor
for CI-AKI (10,12,14), the association between preprocedural blood glucose levels and CI-AKI risk (regardless
of pre-existing diabetes) is unknown. Since nearly 50% of
hyperglycemic AMI patients do not have known diabetes
(22), establishing whether elevated glucose levels before
coronary angiography are related to subsequent CI-AKI risk
would have important clinical implications; primarily by
identifying a previously unrecognized high-risk group that
might benefit from pre-procedural CI-AKI prophylaxis and
also by highlighting a potential target for intervention in the
prevention of CI-AKI.
Accordingly, we analyzed data from the Cerner Corporation’s (Kansas City, Missouri) Health Facts database, a
contemporary registry of patients admitted to 40 hospitals
across the U.S., to define the association between preprocedural hyperglycemia and the risk for CI-AKI during
AMI. This database was selected because of its extensive
collection of laboratory data, including detailed glucose
measurements and assessments of renal function, in a large
consecutive cohort of AMI patients. We specifically sought
to determine the relationship between pre-procedural glucose levels and the risk for subsequent CI-AKI among
patients with and without known diabetes who are referred
for coronary angiography in the setting of AMI.
Abbreviations
and Acronyms
Methods
Data source. Details of the Health Facts database have
been described previously (22). Between January 1, 2000,
and December 31, 2005, the Health Facts database collected deidentified information regarding consecutive patients hospitalized at 40 U.S. medical centers. Variables
included demographics, medical history, and comorbidities
(determined from International Classification of DiseasesNinth Revision billing codes), laboratory studies (including
all venous and fingerstick blood glucose measurements, as
well as all serum creatinine levels during hospitalization),
medications, in-hospital procedures (including coronary
JACC Vol. 55, No. 14, 2010
April 6, 2010:1433–40
angiography and percutaneous coronary intervention
[PCI]), in-hospital mortality, and hospital characteristics
(geographic region, number of beds, surgical and procedural
capabilities, and teaching vs. nonteaching status).
Patient population. We identified all patients hospitalized
with primary discharge diagnoses of AMI (using International Classification of Diseases-Ninth Revision-Clinical
Modification codes 410.xx and excluding 410.x2, which
represents readmission after AMI) who had glucose measurements on admission and at least 1 documented abnormal troponin or creatine kinase-myocardial band level.
Subsequently, those patients who were transferred from or
to other acute care facilities were excluded, as complete
laboratory and medication administration details for the
entire episode of AMI care were not available. For this
analysis, we further restricted the sample to those who
underwent coronary angiography during the AMI hospitalization and whose laboratory studies included at least 1
pre-procedural measurement of serum creatinine and at
least 1 repeat evaluation within 48 h after the procedure. Of
8,786 AMI patients who underwent coronary angiography
during the index hospitalization, 6,358 patients (72%) had
complete pre- and post-procedural laboratory data and
comprised the study cohort.
Glucose assessment and diabetes definition. The Health
Facts database provided access to all of the patients’ glucose
values, including their measurement times. For clarity, all
plasma and capillary glucose measurements are subsequently
referred to as “blood glucose.” The glucose level evaluated
for each patient was the pre-procedural measurement obtained closest to the time of diagnostic angiography. As in
prior studies (22–24), patients were classified as having
recognized diabetes if they had corresponding International
Classification of Diseases-Ninth Revision-Clinical Modification codes or were treated with an oral antihyperglycemic agent or any extended-release insulin during the
hospitalization.
Outcomes. The outcome for this study was the occurrence
of CI-AKI, defined as an absolute serum creatinine increase
ⱖ0.3 mg/dl or a relative increase in serum creatinine ⱖ50%
that occurred within 48 h after coronary angiography, in
accordance with the Acute Kidney Injury Network criteria
(25). The rates of CI-AKI were calculated using pre- and
post-procedural serum creatinine measurements. Preprocedural serum creatinine level was defined as the measurement obtained during hospitalization that occurred
before and closest to the time of coronary angiography.
Post-procedural creatinine level was defined as the highest
serum creatinine measurement within 48 h after coronary
angiography. If a patient underwent more than 1 coronary
angiography procedure, pre- and post-procedural creatinine
levels for the first procedure were considered for this
analysis.
Statistical analysis. Patients were stratified into 5 groups
according to pre-procedural glucose levels: ⬍110 mg/dl,
110 to ⬍140 mg/dl, 140 to ⬍170 mg/dl, 170 to ⬍200
Stolker et al.
Glucose and Contrast-Induced Acute Kidney Injury
JACC Vol. 55, No. 14, 2010
April 6, 2010:1433–40
mg/dl, and ⱖ200 mg/dl. Baseline characteristics were compared among groups using chi-square analysis for categorical variables and analysis of variance for continuous
variables.
Rates of CI-AKI were compared between subgroups of
pre-procedural glucose levels using chi-square analysis, first
in the entire sample and then within the a priori defined
subgroups of patients with and without known diabetes.
Multivariable logistic regression models were subsequently
developed to evaluate whether the association between
pre-procedural glucose values and CI-AKI persisted after
adjustment for other patient characteristics and potential
confounders. In these models, pre-procedural glucose level
was included as a categorical variable, using the 5 groups
described previously. Patient characteristics clinically considered to be prognostically important, and covariates identified in bivariate analyses as predictors of CI-AKI (at a level
of significance of p ⱕ 0.05), were entered into the models.
Covariates included demographic factors (age, gender, and
race), comorbidities (diabetes, heart failure, hypertension,
and cerebrovascular disease), laboratory values (admission
hematocrit and peak troponin value), mechanical reperfusion during hospitalization (coronary artery bypass grafting
[CABG] or PCI), medications during hospitalization (aspirin, clopidogrel, ticlopidine, beta-blockers, calciumchannel blockers, angiotensin-converting enzyme inhibitors
or angiotensin receptor blockers, diuretics, 3-hydroxy-3methylglutaryl coenzyme A reductase inhibitors, oral antihyperglycemic agents, and insulin), hospital site, and hospital length of stay. A pre-procedural glucose ⫻ diabetes
interaction term was also introduced into the models to
formally test whether the glucose-associated risk for CIAKI differed in patients with and without known diabetes.
Importantly, the models also adjusted for the baseline
estimated glomerular filtration rate (GFR), calculated according to the Modification of Diet in Renal Disease study
equation (26). Because contrast volume is a significant factor
in the development of CI-AKI (1), models adjusted for the
performance of PCI (categorized as none, single vessel, or
multivessel), as well as the number of coronary angiography
and PCI procedures during hospitalization (all surrogates of
contrast volume). In addition, to account for pre-procedural
CI-AKI prophylaxis measures, the final models also adjusted for the administration of sodium bicarbonate. Models
were then repeated within the subgroups of patients with
and without diabetes.
Several sensitivity analyses were performed. First, multivariable models were repeated after excluding all patients
who underwent CABG within 48 h of coronary angiography, to ensure that our results were not confounded by the
potential impact of CABG on renal function. Second,
cardiogenic shock was incorporated as a covariate into the
models, given its associations with both hyperglycemia and
CI-AKI (2,19). Third, a different definition of CI-AKI was
used (increase in serum creatinine ⬎0.5 mg/dl or ⬎25%).
1435
Secondary analyses. Additional analyses were performed
to examine whether the relationship between pre-procedural
glucose levels and CI-AKI differed according to baseline
renal function. To accomplish this, patients were divided
into 3 groups according to baseline GFR (⬍30 ml/min, 30
to 59 ml/min, and ⱖ60 ml/min). The rates of CI-AKI were
then compared across the 5 pre-procedural glucose categories (⬍110 mg/dl, 110 to ⬍140 mg/dl, 140 to ⬍170 mg/dl,
170 to ⬍200 mg/dl, and ⱖ200 mg/dl) within each of the
GFR subclasses, using chi-square analysis. These analyses
were then performed separately in patients with and without
diabetes.
A 2-sided p value of ⱕ0.05 was considered statistically
significant. Analyses were conducted with SAS version 8.02
(SAS Institute Inc., Cary, North Carolina). Use of the
Health Facts database was approved by the Saint Luke’s
Mid America Heart Institute Institutional Review Board.
Results
Baseline characteristics. Baseline characteristics are detailed in Table 1, stratified by pre-procedural glucose levels.
Pre-procedural hyperglycemia (glucose ⱖ140 mg/dl) occurred in 42% of the patient sample, and 48% of patients
with elevated glucose before coronary angiography did not
have known diabetes. The median time from pre-procedural
glucose assessment to coronary angiography was 8.3 h
(interquartile range: 5.3 to 16.3 h). Diabetes was present in
1,929 patients (30%). Overall, 823 patients (13%) developed
CI-AKI after coronary angiography. Mean creatinine in
these patients increased from 1.73 ⫾ 1.5 mg/dl at baseline
to a peak of 2.54 ⫾ 1.8 mg/dl, whereas patients without
CI-AKI experienced no significant change in serum creatinine (baseline: 1.16 ⫾ 0.8 mg/dl; post-procedure: 1.14 ⫾
0.7 mg/dl). The median number of post-procedural creatinine measurements was 1 for patients with glucose ⬍110
mg/dl and 2 in all other glucose groups. The median
number of coronary angiograms performed during AMI
hospitalization was 1, and the median number of PCI procedures during hospitalization was 1 across all 5 of the glucose
groups. Overall, 43% of all patients underwent diagnostic
coronary angiography only, 50% underwent single-vessel PCI,
and 7% underwent multivessel PCI. Median hospital length of
stay was 113 h (interquartile range: 74 to 193 h) and is
stratified by glucose level in Table 1.
Compared with patients who had lower pre-procedural
glucose, greater proportions of those with higher glucose were
female and had prior heart failure, AMIs, and diabetes.
Hyperglycemic patients also had lower GFRs, had higher peak
troponin levels and lower hematocrit on admission, and were
treated more frequently with diuretics, angiotensin-converting
enzyme inhibitors or angiotensin receptor blockers, oral antihyperglycemic agents, and insulin. Periprocedural infusions of
sodium bicarbonate, in-hospital PCI, and in-hospital CABG
were used more frequently in patients with higher glucose
levels.
Stolker et al.
Glucose and Contrast-Induced Acute Kidney Injury
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JACC Vol. 55, No. 14, 2010
April 6, 2010:1433–40
Stratified Characteristics
Baseline
by Baseline
Pre-Procedural
of AMI
Glucose
Patients
Concentration
Undergoing
Angiography
(n ⴝ 6,358),(n ⴝ 6,358),
Characteristics
of AMI
Patients Coronary
Undergoing
Coronary Angiography
Table 1
Stratified by Pre-Procedural Glucose Concentration
Glucose Concentration (mg/dl)
Characteristic
<110
(n ⴝ 1,814)
110–<140
(n ⴝ 1,891)
140–<170
(n ⴝ 1,086)
170–<200
(n ⴝ 533)
>200
(n ⴝ 1,034)
p Value
Demographics
Age (yrs)
64 ⫾ 14
64 ⫾ 13
66 ⫾ 13
66 ⫾ 12
65 ⫾ 12
0.002
671 (37)
588 (31)
411 (38)
199 (37)
442 (43)
⬍0.001
1,472 (84)
1,598 (87)
897 (85)
458 (88)
843 (84)
0.024
Hypertension
973 (54)
993 (53)
598 (55)
314 (59)
533 (52)
0.047
Diabetes
225 (12)
311 (16)
344 (32)
278 (52)
771 (75)
⬍0.001
Chronic obstructive lung disease
206 (11)
176 (9)
108 (10)
45 (8)
102 (10)
0.187
Prior AMI
205 (11)
236 (12)
99 (9)
42 (8)
113 (11)
0.008
Prior heart failure
404 (22)
413 (22)
306 (28)
172 (32)
410 (40)
⬍0.001
50 (3)
38 (2)
27 (2)
19 (4)
33 (3)
0.189
110 (6)
96 (5)
58 (5)
31 (6)
39 (4)
0.115
Female
White
Medical history
Prior stroke
Peripheral vascular disease
In-hospital medications
Aspirin
1,609 (89)
1,669 (88)
939 (86)
459 (86)
879 (85)
0.026
Other antiplatelet agent
1,218 (67)
1,365 (72)
766 (71)
368 (69)
697 (67)
0.008
Beta-blocker
1,632 (90)
1,711 (90)
975 (90)
470 (88)
901 (87)
0.049
ACE inhibitor or ARB
1,205 (66)
1,331 (70)
786 (72)
397 (74)
763 (74)
⬍0.001
Calcium-channel blocker
411 (23)
402 (21)
203 (19)
119 (22)
249 (24)
0.033
Diuretic
751 (41)
799 (42)
494 (45)
298 (56)
614 (59)
⬍0.001
0.207
Nitrate
1,467 (81)
1,565 (83)
888 (82)
453 (85)
857 (83)
Statin
1,226 (68)
1,309 (69)
755 (70)
363 (68)
714 (69)
0.777
67 (4)
86 (5)
121 (11)
107 (20)
260 (25)
⬍0.001
271 (15)
327 (17)
283 (26)
212 (40)
620 (60)
⬍0.001
Leukocyte count (⫻1,000/␮l)
10 ⫾ 4
10 ⫾ 7
11 ⫾ 4
11 ⫾ 6
11 ⫾ 4
⬍0.001
Hematocrit (%)
36 ⫾ 14
39 ⫾ 12
38 ⫾ 11
38 ⫾ 10
38 ⫾ 12
⬍0.001
1.26 ⫾ 1.07
1.20 ⫾ 0.84
1.22 ⫾ 0.81
1.35 ⫾ 1.02
1.38 ⫾ 1.09
⬍0.001
Estimated GFR (ml/min)
75 ⫾ 30
75 ⫾ 27
71 ⫾ 28
68 ⫾ 29
67 ⫾ 31
⬍0.001
Peak troponin (ng/ml)
48 ⫾ 164
74 ⫾ 127
78 ⫾ 126
74 ⫾ 133
92 ⫾ 240
⬍0.001
Oral antihyperglycemic agent
Any insulin
Laboratory studies
Baseline creatinine (mg/dl)
In-hospital management
Cardiogenic shock
24 (1)
46 (2)
68 (6)
37 (7)
118 (11)
⬍0.001
Intra-aortic balloon pump
73 (4)
109 (6)
98 (9)
51 (10)
141 (14)
⬍0.001
822 (45)
1,030 (55)
572 (53)
262 (49)
511 (49)
⬍0.001
PCI
Single-vessel
117 (7)
124 (7)
83 (8)
33 (6)
73 (7)
CABG
Multivessel
277 (15)
275 (15)
169 (16)
103 (19)
183 (18)
0.034
Sodium bicarbonate infusion
251 (14)
271 (14)
173 (16)
94 (18)
243 (24)
⬍0.001
117 (75–188)
104 (69–181)
109 (73–197)
131 (83–212)
⬍0.001
Hospital length of stay (h), median (IQR)
130 (82–213)
Categorical variables are expressed as n (%) and continuous variables as mean ⫾ SD, unless otherwise stated.
ACE ⫽ angiotensin-converting enzyme; AMI ⫽ acute myocardial infarction; ARB ⫽ angiotensin receptor blocker; CABG ⫽ coronary artery bypass grafting; GFR ⫽ glomerular filtration rate (by Modification
of Diet in Renal Disease study equation); IQR ⫽ interquartile range; PCI ⫽ percutaneous coronary intervention.
Pre-procedural glucose and CI-AKI. In unadjusted analyses, higher pre-procedural glucose levels were strongly
associated with higher rates of CI-AKI (Table 2). However,
the nature of the relationship between glucose levels and
CI-AKI was significantly different in patients with and
without known diabetes (pre-procedural glucose ⫻ diabetes
interaction p ⬍ 0.001). There was a strong association between
glucose and CI-AKI risk in patients without diabetes (CI-AKI
rates across the 5 glucose groups from lowest to highest: 8.2%,
9.9%, 12.4%, 14.9%, and 24.3%; p ⬍ 0.001). In contrast, no
significant relationship was observed between glucose levels
and CI-AKI in patients with established diabetes (CI-AKI
rates across the 5 glucose groups from lowest to highest:
20.9%, 16.1%, 16.3%, 14.8%, and 19.2%; p ⫽ 0.24).
After adjusting for confounders (including baseline
GFR), the nature of these relationships between glucose
levels and CI-AKI risk persisted (Fig. 1). In patients
without known diabetes, there was a gradual, incremental
increase in the risk for CI-AKI associated with higher
pre-procedural glucose levels (odds ratios [95% confidence
intervals] for glucose groups of 110 to ⬍140 mg/dl, 140 to
⬍170 mg/dl, 170 to ⬍200 mg/dl, and ⱖ200 mg/dl: 1.31
[1.00 to 1.71], 1.51 [1.11 to 2.10], 1.58 [1.03 to 2.43], and
2.14 [1.46 to 3.14], respectively, vs. glucose ⬍110 mg/dl).
Stolker et al.
Glucose and Contrast-Induced Acute Kidney Injury
JACC Vol. 55, No. 14, 2010
April 6, 2010:1433–40
1437
Unadjusted
of CI-AKI
According
Pre-Procedural
Glucose Level
Table 2 Rates
Unadjusted
Rates
of CI-AKItoAccording
to Pre-Procedural
Glucose Level
Glucose Level (mg/dl)
Patient Subgroup
<110
110–<140
140–<170
170–<200
>200
p Value
Entire cohort
177/1,814 (9.8)
207/1,891 (11.0)
148/1,086 (13.6)
79/533 (14.8)
212/1,034 (20.5)
⬍0.001
Patients without known diabetes
130/1,589 (8.2)
157/1,580 (9.9)
Patients with known diabetes
47/225 (20.9)
50/311 (16.1)
92/742 (12.4)
38/255 (14.9)
64/263 (24.3)
⬍0.001
56/344 (16.3)
41/278 (14.8)
148/771 (19.2)
0.24*
Values are expressed as n (%) of patients experiencing CI-AKI. *Interaction term for pre-procedural glucose and diabetes: p ⬍ 0.001.
CI-AKI ⫽ contrast-induced acute kidney injury.
However, no significant increase in glucose-associated risk
for CI-AKI was seen among patients with established
diabetes (corresponding odds ratios [95% confidence intervals]: 0.71 [0.44 to 1.14], 0.82 [0.52 to 1.30], 0.73 [0.45 to
1.12], and 0.94 [0.63 to 1.40]; adjusted p value for glucose
⫻ diabetes interaction ⫽ 0.04). In 3 sensitivity analyses—
first excluding patients who underwent CABG within 48 h
of coronary angiography, second adjusting for the rates of
cardiogenic shock, and third using a different definition of
CI-AKI—the results were similar (data not shown).
Secondary analyses. Among patients without known diabetes, the relationship between pre-procedural glucose levels
and the risk for CI-AKI differed according to baseline GFR
(Fig. 2). There was a graded, significant relationship between higher pre-procedural glucose levels and greater risk
for CI-AKI in patients with GFR ⱖ60 ml/min (CI-AKI
rates across the 5 glucose groups from lowest to highest: 6%,
7%, 9%, 10%, and 18%; p ⬍ 0.001) and in those with GFRs
of 30 to 59 ml/min (11%, 16%, 19%, 18%, and 27%,
respectively; p ⫽ 0.003). However, the relationship between
glucose and CI-AKI was not significant among patients
with severely impaired renal function (GFR ⬍30 ml/min),
as risk remained high regardless of glucose level (CI-AKI
rates across the 5 glucose groups from lowest to highest:
39%, 30%, 33%, 44%, and 44%; p ⫽ 0.66).
Figure 1
Among patients with established diabetes, there was no
significant association between pre-procedural glucose levels
and CI-AKI rates in any of the GFR subgroups (data not
shown).
Discussion
In this large sample of AMI patients undergoing coronary
angiography, we found that the nature of the relationship
between pre-procedural glucose levels and the risk for
CI-AKI was markedly different among patients with and
without established diabetes. Elevated glucose was common
and associated with a steep incremental increase in the risk
for CI-AKI after coronary angiography among patients who
did not have known diabetes. In contrast, no such association was observed among patients with established diabetes,
who experienced high CI-AKI rates regardless of preprocedural glucose levels. Importantly, glucose-associated
CI-AKI risk was as high or even higher in patients without
diabetes who had significant pre-procedural hyperglycemia,
as in those with established diabetes. Moreover, the relationship between higher pre-procedural glucose and greater
CI-AKI risk was particularly pronounced in those patients
without diabetes who did not have significantly impaired
renal function, a group that is not currently considered to be
at high risk for CI-AKI. Our findings imply that, at a
Glucose and Risk of CI-AKI
Relationship between pre-procedural glucose levels and risk for contrast-induced acute kidney injury (CI-AKI) after coronary
angiography in acute myocardial infarction patients with and without known diabetes after multivariate adjustment. CI ⫽ confidence interval.
1438
Figure 2
Stolker et al.
Glucose and Contrast-Induced Acute Kidney Injury
JACC Vol. 55, No. 14, 2010
April 6, 2010:1433–40
Glucose and CI-AKI Rates Across GFR Subgroups
Relationship between pre-procedural glucose levels and contrast-induced acute kidney injury (CI-AKI) across subgroups of
glomerular filtration rate (GFR) (calculated using the Modification of Diet in Renal Disease study equation) in patients without known diabetes.
minimum, hyperglycemic patients without known diabetes
should be recognized as a high-risk group for CI-AKI and
should be considered for prophylactic measures similar to
those used in other high-risk patients.
Prior studies of hyperglycemia. This study is the first, to
our knowledge, to demonstrate that elevated pre-procedural
glucose levels are associated with increased risk for CI-AKI
in AMI patients without diabetes undergoing coronary
angiography. However, the relationship between hyperglycemia and renal injury has been previously described in
other patient populations. Specifically, prior studies have
demonstrated a relationship between higher glucose levels
and greater risk for acute renal failure among critically ill
patients hospitalized in intensive care units (27). Elevated
pre- and perioperative glucose levels are also independently
associated with higher risk for post-operative renal dysfunction among patients undergoing cardiac surgery (28,29); in
fact, pre-operative glucose ⬎140 mg/dl has been incorporated into a prediction model of post-operative kidney injury
in this patient population (28). A few relatively small,
single-center studies also suggested that pre-diabetes may
increase the risk for contrast-induced nephropathy in patients with chronic kidney disease who undergo elective
coronary angiography (30) and that metabolic syndrome
may increase the risk for acute renal failure in patients with
AMIs (31). Our study adds substantially to these data by
demonstrating in a large, multicenter cohort that preprocedural hyperglycemia markedly elevates the risk for
CI-AKI in patients without established diabetes, even after
accounting for baseline renal function and a multitude of
other factors.
Clinical implications. Our findings have several potentially important clinical implications. First, although diabetes is a well-known predictor of contrast nephropathy
(10,12,14), elevated pre-procedural glucose levels in patients
without established diabetes are not currently recognized by
clinicians as a risk factor for contrast-mediated renal injury.
Since hyperglycemia occurs in over 40% of AMI patients,
nearly half of whom have no known diabetes (19,22,32),
this group of patients should at least be considered to be at
as high a risk for CI-AKI as those with established diabetes.
CI-AKI prophylaxis may need to be considered in these
patients, as well as careful monitoring of post-procedural
renal function. Second, elevated pre-procedural glucose may
represent a modifiable intervention target for CI-AKI
prevention. Whether hyperglycemia is a marker of increased
comorbidity burden and disease severity or a direct mediator
of CI-AKI is unknown, but prior studies have demonstrated
increased oxidative stress, blunting of free radical scavengers, decreased levels of nitric oxide, and endothelial dysfunction in the setting of elevated glucose (33– 42). Other
investigators have shown enhanced susceptibility to ischemic and reperfusion injury in animal models of experimentally induced hyperglycemia (43). Since numerous studies
have shown that similar pathophysiologic mechanisms are
also involved in contrast nephropathy (3,14,15), the effects
of hyperglycemia in our analysis may reflect a “double insult”
to renal function that previously has not been described in
patients without established diabetes. Although no conclusions regarding a possible cause-and-effect relationship between hyperglycemia and CI-AKI can be drawn from our
study, several randomized trials in critically ill patients have
demonstrated that glycemic control with insulin may reduce
the rates of acute renal failure (44 – 46). Because the findings
of these clinical trials cannot be automatically extrapolated
to AMI patients undergoing coronary angiography, prospective randomized studies are needed to determine
whether glucose control can reduce the rates of CI-AKI in
the setting of AMI.
The reasons behind the different relationships between
glucose levels and CI-AKI risk among patients with and
without known diabetes are unclear but have been previously described with other outcomes, such as mortality
(19 –22). Several possible explanations exist for this phenomenon. First, as previously demonstrated in other studies
(19,32), hyperglycemic AMI patients without known dia-
JACC Vol. 55, No. 14, 2010
April 6, 2010:1433–40
betes typically receive much less aggressive therapy for
glucose control compared with those who have known
diabetes. Since intensive glucose control with insulin has
been previously shown to reduce the rates of renal injury in
critically ill patients (44,46,47), this significant discrepancy
in treatment rates may have an effect on glucose-associated
CI-AKI rates. Second, since diabetes is a well-recognized
risk factor for CI-AKI, patients with diabetes may receive
more aggressive pre-procedural CI-AKI prophylaxis, attenuating the potential effect of hyperglycemia on renal injury.
Third, some hyperglycemic AMI patients without known
diabetes (particularly those with glucose ⬎200 mg/dl) may
actually have diabetes that has been neither recognized nor
adequately managed and thus may represent a higher-risk
cohort for the development of CI-AKI. Even if not definitively
diagnosed with diabetes by hospital discharge, hyperglycemia
in AMI patients likely represents glucose dysmetabolism, and
the simple act of evaluating pre-catheterization glucose should
alert clinicians to the elevated risk for renal injury. Finally, it
is also possible that a greater degree of stress (illness
severity) is needed for patients without established diabetes
to achieve the same degree of hyperglycemia as their
counterparts with diabetes. However, the difference in the
association between hyperglycemia and CI-AKI among
patients with and without known diabetes persisted even
after accounting for disease severity indicators, including
infarct size.
Study limitations. The results of our study should be
interpreted in the context of several potential limitations.
First, the volume of contrast administered in each procedure
was not available; however, we believe that by using the
performance of PCI (including the differentiation between
single-vessel and multivessel PCI) in the multivariable
models, we introduced a surrogate for presumed higher
contrast volume (compared with diagnostic angiography
alone). Moreover, there is no a priori reason to expect that
hyperglycemic patients would be more likely to receive
larger or smaller doses of contrast material than normoglycemic patients. Second, although we rigorously attempted
to account for baseline differences between patients in
different pre-procedural glucose groups, residual confounding cannot be excluded. Specifically, we were unable to
control for certain clinical variables, such as the presence of
ST-segment elevation and left ventricular ejection fraction.
However, adjustment for ST-segment elevation and ejection fraction did not affect the nature of glucose-associated
risk for mortality in our prior studies (19), and we were able
to control for other variables, such as infarct size (using peak
troponin levels) and numerous other patient factors. Third,
our data are limited to AMI patients undergoing angiography, and the relationship between hyperglycemia and CIAKI in other patient populations or with other diagnostic
modalities requiring intravenous contrast (e.g., computed
tomography scans, other angiograms) remains unclear.
Fourth, we do not know how many of those patients
without known diabetes were subsequently diagnosed with
Stolker et al.
Glucose and Contrast-Induced Acute Kidney Injury
1439
diabetes after discharge; however, our specific focus was to
evaluate the CI-AKI risk associated with pre-procedural
glucose values in patients who were not recognized as
having diabetes at the time of AMI hospitalization. Finally,
although we adjusted for sodium bicarbonate administration
in our analyses, we were unable to determine whether
glucose lowering with insulin or the use of other prophylactic CI-AKI therapies (e.g., intravenous hydration or
N-acetylcysteine) could reduce the risk for CI-AKI in
hyperglycemic AMI patients without established diabetes.
This will need to be determined in future prospective
investigations.
Conclusions
In summary, elevated pre-procedural glucose levels are
associated with greater risk for CI-AKI in AMI patients
without established diabetes who undergo coronary angiography. Close monitoring of post-procedural renal function
and prophylactic therapies used to prevent CI-AKI should
be considered in this patient group.
Reprint requests and correspondence: Dr. Mikhail Kosiborod, Mid
America Heart Institute of Saint Luke’s Hospital, 4401 Wornall Road,
Kansas City, Missouri 64111. E-mail: [email protected].
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Key Words: contrast nephropathy y acute kidney injury y glucose y
diabetes y myocardial infarction y coronary angiography.