Relation between acute hyperglycemia and contrast-induced
nephropathy (CIN) in patients undergoing primary
percutaneous coronary intervention (PPCI)
Yehia Kishk, Hamdy Soliman, Mahmoud Abdelsabour, Ahmed
Mostafa Magdy.
Abstract:
Background: In a patient with ST-elevation myocardial infarction
(STEMI), acute hyperglycemia is frequently encountered on presentation.
Contrast-induced nephropathy (CIN) is also a common complication in those
undergoing primary percutaneous coronary intervention (PPCI). We
investigated the possible association between on-admission hyperglycemia
and CIN in STEMI patients undergoing PPCI.
Methods: This study included 60 patients that presented to the emergency
department with STEMI who underwent PPCI. They were investigated for
on-admission acute hyperglycemia defined as serum glucose > 198mg/dl,
and subsequent CIN, defined as either ≥ 25% increase or ≥ 0.5 mg/dl
absolute increase of on-admission baseline serum creatinine level within 4872 hours of radio-contrast administration.
Results: Overall 37% of STEMI patients had acute hyperglycemia, and
35% developed CIN. Patients with on-admission hyperglycemia had 10
times the risk of developing CIN compared with normoglycemic patients.
In-hospital mortality occurred more frequently in patients with acute
hyperglycemia (13.6%) and CIN (14%). Patients with acute hyperglycemia
that developed CIN had the highest mortality rate (21.4%).
Conclusion: In STEMI patients undergoing PPCI, those with acute
hyperglycemia are at high risk of CIN and in-hospital mortality.
Introduction:
PPCI is effective in securing and maintaining coronary artery patency.
Randomized clinical trials comparing timely performed PPCI with inhospital fibrinolytic therapy have shown more effective restoration of
patency, less re-occlusion, improved residual left ventricular function and
better clinical outcome with primary PCI.(1)
In patients undergoing PPCI, short- and long-term mortality rates were
significantly higher in those who developed CIN. CIN is also associated
with other post-PPCI adverse outcomes including MI and target vessel
revascularization, bleeding requiring transfusion, and vascular
complications).(2)
Acute hyperglycemia occurs in about half of patients with STEMI, while
about 25% has diabetes mellitus.(3) Acute hyperglycemia on admission has
been reported to worsen the prognosis in AMI patients with and without
known diabetes.(4,5) Hyperglycemia is usually due to insulin resistance and
accelerated glucose production, known as ‘stress diabetes’ or ‘diabetes of
injury’.(6)
Several mechanisms of hyperglycemia during AMI have been postulated.
These include enhanced oxidative stress, activation of blood coagulation and
platelets, stimulation of inflammation, and endothelial cell dysfunction.(7)
Several STEMI studies have reported that acute hyperglycemia is
independently associated with acute increase in inflammatory immune
markers, lower rate of TIMI flow grade 3 after primary stent implantation,
"no-reflow" phenomenon, increased left ventricular dysfunction, larger
infarct size, higher risk of congestive heart failure and cardiogenic shock,
and increased hospital mortality.(8)
Potential pathophysiologic mechanisms through which contrast
administration may cause renal injury include oxidative stress, endothelial
dysfunction, and apoptosis.(9) All these processes are also activated in the
setting of acute hyperglycemia.(10)
In the present study, we tried to examine the effect of the on-admission
glucose levels and the risk of subsequent CIN in patients with STEMI who
undergo PPCI. In-hospital mortality rate and other major adverse cardiac
events (MACE) were also evaluated.
Methods:
Study population:
This prospective observational study was conducted at the National heart
institute, in Cairo in collaboration with the cardiology department of Assiut
University, between August 2011 and November 2012. We enrolled 60
patients that presented with STEMI and underwent PPCI.
Patients were included if they presented within 12 hours and 18 hours for
AMI complicated with cardiogenic shock from onset of symptoms. The
diagnosis of AMI was based on characteristic chest pain lasting for at least
30 minutes, not responsive to nitrates, with electrocardiographic ST-segment
elevation of at least 0.1 mV in two or more contiguous leads, or new left
bundle-branch block.
Patients on long-term dialytic treatment were excluded. Patients with
recent exposure to radiographic contrast (within two days of the study) were
also excluded. Patients undergoing cardiac surgery for emergency coronary
revascularization and/or mechanical complications were excluded from the
analysis. The Ethical Committee of both Institutes approved the study, and
written informed consents were obtained.
Study design:
In all patients, plasma glucose levels were assessed at hospital admission;
and acute hyperglycemia was defined as glucose levels >198 mg/dl,
regardless of the diabetic status.(11,12) Patients were recognized as having
DM if they had a history of DM with the use of oral hypoglycemic agents or
insulin. Serum creatinine concentration was measured at hospital admission,
every day for the following 3 days, at discharge from the coronary care unit,
and at hospital discharge.
Glomerular filtration rate (eGFR) was estimated using the modified
formula of cockroft, and preprocedural renal insufficiency was categorized
as an eGFR <60 mL/(min 1.73 m2). Contrast-induced nephropathy was
defined as an increase in creatinine >25% or an absolute increase of 0.5
mg/dl or more from the baseline value within the 72-hour period following
PPCI.(13-15)
Pharmacologic therapy during and after PPCI was left to the discretion of
the interventional and CCU cardiologists, based on current standards of
care.(16)
PCI Procedure:
Heparin (10,000 U) was administered after coronary anatomy was
defined. Coronary artery stenosis > 70% was considered clinically
significant. PPCI was performed by a 24-hours on-call interventional team.
Balloon angioplasty and/or stent implantation were performed only for IRA
with successful mechanical restoration of antegrade flow in all patients. A
non-ionic, low-osmolality contrast agent was used and the amount of
contrast used in every procedure was reported.
Statistical Analysis:
The collected data was revised, coded, tabulated and introduced to a PC
using Statistical package for Social Science (SPSS 15.0.1 for windows;
SPSS Inc, Chicago, IL, 2001).
i. Descriptive statistics:
1. Mean, Standard deviation (± SD) and range for parametric numerical
data.
2. Frequency and percentage of non-numerical data.
ii. Analytical statistics:
1. Student T Test was used to assess the statistical significance of the
difference between two study group means.
2. Correlation analysis (using Pearson's method): To assess the strength
of association between two quantitative variables. The correlation coefficient
denoted symbolically "r" defines the strength and direction of the linear
relationship between two variables.
3. Chi-Square test was used to examine the relationship between two
qualitative variables.
4. Fisher’s exact test: was used to examine the relationship between two
qualitative variables when the expected count is less than 5 in more than
20% of cells.
5. Logistic regression: useful in the prediction of the presence or absence of
an outcome based on a set of independent variables. It is similar to a linear
regression model but is suited when the dependent variable is qualitative
(categorical).
-P- value: level of significance
-P>0.05: Non significant (NS).
-P< 0.05: Significant (S).
-P<0.01: Highly significant (HS).
RESULTS
This study included 60 patients (48 males and 12 females) with age
ranging from 27 to 85 years with a mean of 54.5±11.6 years. There were 21
hypertensive (35%) and 26 diabetic (43.3%) patients.
There was no significant difference between normoglycemic and
hyperglycemic patients on admission as regard risk factors, as about 55% of
hyperglycemics were diabetic while about 37% of normoglycemics were
also diabetics, this was statistically insignificant, as well as the other risk
factors.
100%
90%
80%
Percent
70%
60%
50%
40%
30%
20%
10%
0%
Smoker
Dyslipidaemia
DM
HTN
IHD
Risk factors
Figure (1) Risk factors among patient population.
Ejection fraction, admission serum creatinine and GFR among
studied patients:
The mean ejection fraction (estimated by echocardiography) after
intervention was 48.5 + 8.2 %.
The mean baseline serum creatinine level of the studied population was 1.03
+ 0.25 mg/dl, while the mean GFR was 89.9 + 32 (12 patients (20%) had
GFR<60).
Mean
±SD
Minimum
Maximum
LVEF (%)
48.47
8.16
35.00
68.00
Admission serum creatinine (mg/dl)
1.03
.25
.60
1.89
GFR (mL/min/m²)
32.00
210.00
GFR<60
89.87
32.00
Yes (n %)
12
20.0%
No (n %)
48
80.0%
Table (1) LVEF and admission renal function of the patients.
Twenty two out of 60 (36.6%) patients presented with on-admission acute
hyperglycemia.
37%
63%
Hyperglycemia
No
Yes
Figure (2) Percentage of patients presenting with hyperglycemia.
In-hospital complications and MACE:
During hospital stay AF was recorded in 3 patients (5%), while 6 patients
(10%) suffered VF. Cardiogenic shock was present in 4 patients, while 5
patients were mechanically ventilated.
CIN occurred in 21 (35%) patients, of them 2 patients required
hemofilteration. Overall, in-hospital mortality of the study population was
5% (n=3).
In-hospital complications in relation to the presence or absence
of hyperglycemia:
Hyperglycemia
Nº of
cases
No
P*
Sig
Yes
Nº
%
Nº
%
AF
3
1
2.6%
2
9.1%
.548*
NS
VF
6
1
2.6%
5
22.7%
.021*
S
Cardiogenic shock
4
0
.0%
4
18.2%
.015*
S
Mechanical ventilation
5
0
.0%
5
22.7%
.005*
HS
CIN
21
7
18.4%
14
63.6%
.001**
HS
Dialysis
2
0
.0%
2
9.1%
.131*
NS
Mortality
3
0
.0%
3
13.6%
.045*
S
*Fisher exact test
**Chi square test
Table (2) In-hospital complications in relation to the presence or absence of
hyperglycemia.
CIN occurred in 14 patients (63.6%) with on-admission acute
hyperglycemia, and in 7 patients (18.4%) without.
All in-hospital complications (VF, mechanical ventilation, cardiogenic
shock and mortality) were significantly more frequent among patients with
hyperglycemia than those without.
100%
90%
80%
70%
Percent
60%
50%
40%
30%
20%
10%
0%
Hyperglycemic
Normoglycemic
CIN
No CIN
Figure (3) Incidence of CIN in hyperglycemic and normoglycemic patients.
In-hospital complications in patients with and without CIN:
Patients who suffered CIN were more prone to in-hospital complications and
mortality.
CIN
Nº of cases
No
Yes
P*
Sig
Nº
%
Nº
%
AF
3
1
2.6%
2
9.5%
.278*
NS
VF
6
1
2.6%
5
23.8%
.017*
S
Cardiogenic shock
4
0
0%
4
19.0%
.012*
S
Mechanical ventilation
5
0
0%
5
23.8%
.004*
HS
Dialysis
2
0
0%
2
9.5%
.119*
NS
3
0
0%
3
14.3%
.039*
S
Mortality
*Fisher exact test
**Chi square test
Table (3) Differences among patients with CIN regarding in-hospital MACE.
100%
Percent
80%
60%
40%
20%
0%
CIN
No CIN
Lived
Died
Figure (4) Relation between CIN and mortality.
Multiple regression analysis to assess the association between
acute hyperglycemia and CIN after adjustment of other
patients’ characteristics:
B
P
Sig.
Hypertension
3.028
.130
NS
.722
12.695
Dyslipidaemia
3.548
.099
NS
.789
15.964
.108
NS
.455
2783.262
.985
1.052
Admission serum creatinine
35.593
95.0% C.I.for EXP (B)
GFR
1.018
.291
NS
Hyperglycemia
10.275
.002
HS
2.340
45.109
.838
NS
.264
5.164
DM
1.167
Table (4) Association between hyperglycemia and CIN after adjustment of other
patients’ characteristics.
After adjustment of all confounding variables, patients with admission
hyperglycemia have 10 times the risk of developing CIN compared to
normoglycemic patients.
DISCUSSION
The results of the present study showed that acute hyperglycemia in
STEMI patients undergoing PPCI is a significant and independent predictor
of CIN and poor in-hospital outcome.
The study included 60 patients with STEMI who were treated with PPCI.
Neither age nor sex differences had a significant effect on the incidence of
CIN.
Acute hyperglycemia is common in patients with STEMI, even in the
absence of a history of type 2 DM.(17) Even mild hyperglycemia has adverse
prognostic implications in patients with acute myocardial infarction. (18)
Stranders et al (2004) reported that, for every 18-mg/dl (1-mmol/L) increase
in glucose level, there is a 4% increase in mortality in nondiabetic
patients.(19) Moreover, for the same increase in glucose level, an adjusted
increase in mortality risk of 10% has been reported for STEMI patients
undergoing PPCI.(20)
Acute hyperglycemia is associated with several adverse effects Which
include endothelial dysfunction, increased cytokine activation, increased
oxidative stress, impaired microcirculatory function as manifested by postPCI "no-reflow" phenomenon, and impaired ischemic preconditioning.(21)
Hyperglycemia has also several prothrombotic effects such as enhanced
thrombin formation, platelet activation, and fibrin clot resistance to lysis that
may contribute to an increased risk for thrombotic complications.(22)
In our study population, 22 out of 60 patients presented with acute
hyperglycemia. Contrast-induced nephropathy occurred in 21 (35%)
patients, while 2 patients required hemofilteration. Overall, in-hospital
mortality of the study population was 5% (n = 3).
In the current study, all in-hospital complications occurred more
frequently in the hyperglycemic group. VF occurred in 23%
of
hyperglycemic patient Vs. 3% in non-hyperglycemics. Mechanical
ventilation was required in 23% of hyperglycemics Vs. 0% in nonhyperglycemics. Furthermore, cardiogenic shock and mortality occurred in
18% and 14% of hyperglycemic patients (respectively).
Oxidant stress-mediated injury and renal medullary hypoxia and
ischemia, due to vasoconstriction in response to contrast medium
administration, have been implicated as causative factors for CIN.(23)
Moreover, acute hyperglycemia may induce osmotic diuresis, resulting in
volume depletion and dehydration and further increasing CIN risk and
severity.
Marenzi et al (2010) reported that, patients with acute hyperglycemia
had a 2-fold higher incidence of CIN than those without. Furthermore, there
was 40% in-hospital mortality in patients with acute hyperglycemia who
developed CIN. Surprisingly, among patients with acute hyperglycemia,
CIN rate was higher in nondiabetic than in diabetic patients (38% vs 16%, P
= .003).(24)
In our study, contrast-induced nephropathy occurred in 14 patients
(63.6%) with acute hyperglycemia, compared with 7 patients (18.4%) in
those without acute hyperglycemia. There was also positive correlation
between on-admission serum glucose levels and serum Creatinine. Worth
mentioning is that the contrast volume used was nearly equal in both groups.
There was positive correlation between admission serum glucose level
and the incidence of CIN, which is also the case with admission serum
creatinine. Also, in this study group, hypertension and dyslipidemia had
positive correlation with the incidence of CIN.
The importance of a tight control of hyperglycemia as a strategy for
improving prognosis in STEMI patients and, in general, in all critically ill
patients is still under debate. Growing evidence, however, suggests that
control of hyperglycemia during acute illness among diabetic and nondiabetic patients may be associated with improved outcome.(25) Van den
Berghe et al (2001) showed that, in 1,548 surgical ICU patients, those
rendered relatively euglycemic with insulin infusion had a 41% reduction of
renal failure requiring a renal replacement therapy (4.8% vs 8.2%, P = .007)
and a lower incidence of acute kidney injury (9% vs 12.3%, P = .04).(26)
These findings underline the importance of control of acute hyperglycemia
as a possible prophylactic strategy for prevention of CIN in STEMI patients
undergoing primary PCI.
After adjustment of all confounding variables in the present study,
patients with on-admission hyperglycemia have 10 times the risk of
developing CIN compared with normoglycemic patients.
The current study had the following limitations:
 The sample size was rather small and the follow-up time was shortterm.
 The causal relationship between acute hyperglycemia and CIN
remains uncertain. However, multivariate analysis showed that acute
hyperglycemia was an independent predictor of CIN after adjustment
for major clinical variables associated with infarct size and with
development of acute kidney injury.
 There was no standard hydration procedure for prevention. And also
we do not have enough information about the percentage of use of
ACE-Is, ARBs, and diuretics.
 Finally, the lack of screening for patients with newly detected diabetes
and with impaired glucose tolerance, and of measurement of glycated
hemoglobin A1c, which would have provided some insights into the
possible relationship of acute versus chronic hyperglycemia and CIN
risk, represents further limitations of our study.
Recommendations





Based on the results of our study, future research should focus on the
effect of prophylactic strategies based on tight glycemic control in
prevention of CIN and improvement of the clinical outcome of
patients with STEMI.
Identification of high risk patients for CIN to make all attempts at the
time of intervention to prevent CIN, including adequate hydration,
minimization of contrast use, use of low-osmolar contrast, and
possibly administration of N-acetylcysteine.
Monitoring of the patients that underwent PPCI for CIN, by daily
serum creatinine in the CCU, which is sometimes missed by the junior
staff.
Dehydration should be avoided; hydration has been proven to be safe,
cheap, effective and rapid method that can be easily applied to all
patients and during emergency (e.g. PPCI). Therefore prophylaxis is
crucial, especially in patients considered to be at high risk for CIN.
Careful use of nephrotoxic drugs that are routinely used in CCU after
PPCI (e.g. ACEI, LMWHs), and modification or omission of the
doses according to kidney functions.
Conclusion
Based on the results of the current study it can be concluded that:
In STEMI patients treated with primary PCI, acute hyperglycemia is closely
associated with CIN risk and in-hospital morbidity and mortality.
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