Background: Patients undergoing primary PCI are at high risk for contrast-induced nephropathy (CIN), a complication that has a serious impact on in-hospital outcome.  Acute hyperglycemia is common in patients with STEMI even in the absence of history of DM and has been identified as a major predictor of in-hospital mortality and morbidity.

Objective: To determine the association between admission acute hyperglycemia and the risk of subsequent CIN in patients with STEMI undergoing primary PCI.

Patients and Methods: The study included 120 patients who presented with acute STEMI and were treated with primary PCI. The patients were divided into 2 groups:

Group A:  Included (60) patients with acute hyperglycemia (blood glucose >198 mg/dl)

Group B:  Included (60) patients without acute hyperglycemia on admission.

Serum creatinine was measured at the time of admission and daily for the following 5 days. CIN was defined as an increase of ≥25% or an absolute increase of ≥0.5 mg/dl in serum creatinine level

Results: There was a statistically significant difference regarding the incidence of CIN and need for dialysis between both groups, where CIN occurred in 23 (38.3%) patients, of which 9 patients required dialysis in group A, while in group B, CIN occurred in 8 (13.3%) patients, of which none needed dialysis (P < 0.01).

In-hospital adverse events occurred more frequently in group (A) than group (B). In Group (A) 9 patients (15%) had acute pulmonary oedema (APO), cardiogenic shock and needed mechanical ventilation. On the other hand in Group (B) 2 patients (3.3%) had APO and 1 patient (1.7%) had cardiogenic shock and required mechanical ventilation (P< 0.05)
Overall in-hospital mortality of the study population was 10% (n = 6) all of which were in group (A) (P < 0.05).

Conclusion: In patients undergoing primary PCI, acute hyperglycemia is associated with increased incidence of CIN as well as increased incidence of in-hospital adverse events and in-hospital mortality.

Keywords: contrast-induced nephropathy, cin, acute hyperglycemia, primary pci, stemi

PCI, percutaneous coronary intervention; CIN, contrast-induced nephropathy; STEMI, ST-segment elevation myocardial infarction

Patients undergoing primary percutaneous intervention (PCI) are at high risk for contrast-induced nephropathy (CIN), a complication that has a serious impact on in-hospital outcome and may affect the overall benefit of primary PCI. In-hospital mortality has been shown to be 20 times higher in patients who experience CIN after primary PCI.¹ Oxidant stress-mediated injury and renal medullary hypoxia and ischemia, due to endothelial dysfunction and vasoconstriction as well as enhanced apoptosis in response to contrast medium administration, have been implicated as causative factors for CIN.² All these processes are also activated in the setting of acute hyperglycemia and there is clear evidence that marked fluctuations in glucose levels have consequences that are even more deleterious than those of chronically elevated glucose.³ Acute hyperglycemia (defined as glucose levels >198 mg/dL (11 mmol/L),⁴ is common in patients with STEMI, even in the absence of history ofdiabetes mellitus (DM).⁵ Increased glucose levels at hospital presentation has been identified as a major independent predictor of both in-hospital mortality and congestive heart failure in patients presenting with STEMI even in those without pre-existing DM.^6,7 The present study aimed at determining the association between acute hyperglycemia (regardless of pre-existing diabetic status) and the risk of subsequent development of CIN in patients presenting with STEMI treated by primary PCI.

This study prospectively enrolled 120 patients who presented to the emergency department of the National Heart Institute (NHI) diagnosed with a first attack of acute ST-elevation myocardial infarction according to the universal definition of MI.⁸ The study was approved by the Ethics committee of Ain Shams University. The objectives of the project and study design were explained completely to the participants and informed consent was obtained from them as well as they were ensured their data would remain private.

The study included patients presenting within 12 hours from the onset of symptoms (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) and were treated with primary PCI in at timely fashion (door to balloon time < 90 minutes).

The patients were divided into 2 groups according to presence of acute hyperglycemia (blood glucose >198 mg/dl on admission):⁴

1. Group A: Which included (60) patients with acute hyperglycemia.
2. Group B:  Which included (60) patients without acute hyperglycemia.

The following patients were excluded from the study: Patients with history of pre-existing renal diseases, those with baseline creatinine clearance ≤30 ml and patients on regular renal dialysis. Patients who underwent cardiac surgery for emergency coronary revascularization and/or mechanical complications or patients who died during PCI were also excluded from the study.

The patients were subjected to

1. Proper history taking and examination

 All patients were subjected to thorough history taking, full clinical examination including general and local cardiac examination and 12 lead E.C.G.

2. Laboratory investigations

Admission serum glucose level was measured.  Serum creatinine was measured at the time of admission (baseline venous sample of serum creatinine withdrawn prior to the primary PCI procedure) and every day of the following five days during hospital stay and the GFR was calculated by cockcroft-Gault formula.⁹ Contrast-induced nephropathy was defined as impairment of renal function occurring within 48 hours after administration of contrast medium, manifested by an increase in serum creatinine level of 0.5 mg/dl or by a relative increase of 25% over the baseline value.¹⁰

3. Echocardiography

A standard trans-thoracic echocardiographic evaluation was performed to all patients after hospital admission with special emphasis on the left ventricular ejection fraction by modified Simpson’s method.

4. Coronary angiography and 1ry PCI

All patients received chewable aspirin (300 mg) and clopidogrel (600 mg loading dose) before coronary angiography. Primary PCI was performed by a 24-hour on-call interventional team, according to standard clinical practice, including balloon angioplasty and/or stent implantation were performed only for IRA according to lesion anatomy, with successful mechanical restoration of antegrade flow and achieving the desired end results. After Primary PCI; IRA flow was graded according to the Thrombolysis in Myocardial Infarction (TIMI) flow classification (TIMI 0, 1, 2, 3)¹¹ and myocardial reperfusion was graded according to Myocardial Blush Grade (MBG) classification (MBG 0, 1, 2, 3)¹² The type of contrast used was Ioversol (Optiray 300)® which is a low osmolar non ionic contrast media and volume of contrast medium used in every procedure was reported. After angioplasty, all patients were admitted to the coronary care unit, where standard guideline directed medical treatment was continued.

During hospitalization the following adverse clinical events were reported:

1. Acute pulmonary edema and mechanical ventilation.
2. Acute renal failure requiring emergency hemodialysis.
3. Cardiogenic shock.
4. Arrhythmias and death.

Statistical analysis

Data was analyzed using IBM SPSS v.21. Continuous variables were summarized in the form of mean ± SD. Categorical variables in the form of count and percentages.  Statistical analysis tests include unpaired t-test for metric variables and Chi Square test for categorical ones. Logistic regression was used to assess the significance of individual variables while fixing for others. P- values <0.05 were considered significant.

Baseline demographic, clinical, laboratory and echocardiographic data

Table 1 summarizes the baseline demographic, clinical, laboratory and Echocardiographic data of both studied groups (p value > 0.05).  Age, weight and prevalence of DM were statistically higher in group A (p value= 0.016, 0.022 and 0.001 respectively), however there was no statistically significant difference between the two groups regarding rest of risk factors, baseline EF or baseline kidney function (p value > 0.05).

Procedural data

There was no statistically significant difference between the two studied groups regarding the type of infarction & infarct related artery (IRA), symptom to balloon time as well as the volume of contrast used (p value > 0.05). Although there was no statistically significant difference between the 2 studied groups regarding the final TIMI flow grade (p value = 0.174), however the MBG was statistically significantly lower in group A (p=0.025) (Table 2).

Renal functions and incidence of CIN

There was no statistically significant difference between the two studied groups regarding the baseline serum creatinine level & estimated GFR on admission (p value > 0.05). However there was a statistically highly significant difference between the two groups regarding the maximum recorded creatinine during hospital stay, being higher in group A (1.5+0.9mg/dl in group A vs 1.1+0.2 mg/dl in group B) (p = 0.001) (Table 3 & Figure 1).

Figure 1 Comparison between the two studied groups regarding incidence of CIN & need for dialysis.

There was also a statistically significant difference between the two groups regarding the estimated GFR of maximum creatinine during hospital stay, (74.5+34.9 ml/min in group A vs 90.5+31.4ml/min in group B) (p<0.05).  The timing of peak creatinine during hospital stay was nearly equal in both groups with no statistically significant difference (3.8+0.8 day in group A vs 3.5+0.5 day in group B) (p> 0.05). There was a highly statistically significance difference regarding the incidence of CIN and need for dialysis between both studied groups, where CIN occurred in 23 (38.3%) patients, of which 9 patients required dialysis in group A, while in group B, CIN occurred in 8 (13.3%) patients, none of which needed dialysis (p < 0.01).

In-hospital complications and mortality

In-hospital adverse events occurred more frequently in the group (A) than in group B (Table 4). The incidence of Ventricular tachycardia/ventricular fibrillation (VT/VF), Acute pulmonary oedema (APO) cardiogenic shock & need for mechanical ventilation were significantly higher in group (A) (p < 0.05). Overall in-hospital mortality of the study population was 10% (n = 6) in group (A), while in group (B) no mortality was recorded (p value = 0.013). Logistic regression was used to assess the relationship between CIN and each of acute hyperglycemia, age, weight and diabetic status.  The odds of having CIN was 3.85 times more for patients presenting with acute hyperglycaemia than in the control group (p: 0.007, OR 95%CI: 1.45-10) while adjusting for all other variables.  For age, the odds of having CIN were 1.05 times more for each one-year increase in age. (p: 0.034, OR 95%CI: 1.003-1.01). The other two variables (weight and diabetic status) were non-significant as shown in Table 5.

In the present study, the presence of acute hyperglycemia in STEMI patients undergoing primary PCI, was associated with a significant increase in incidence of CIN and need for dialysis. The association between high glucose levels and acute kidney injury is supported by previous studies.^13-15 Marinzi et al.¹⁶ in 2010showed that in STEMI patients treated with primary PCI, acute hyperglycemia was an independent predictor of CIN, where patients with acute hyperglycemia had a 2-fold higher incidence of CIN than those without acute hyperglycemia (p<0.001) (27% vs 12%, P < 0.001). Contrast induced nephropathy requiring hemofiltration was also significantly higher in patients with acute hyperglycemia (6% vs 2% p = 0.005).¹⁶

In the present study, hyperglycemia associated increased CIN risk and need for dialysis occurred regardless of the Diabetic state. Surprisingly, Diabetes mellitus itself was not a statistically significant risk factor for CIN. Similar results were reported by Marenzi et al.¹⁶ who found that  CIN rate  among patients with acute hyperglycemia, was higher in nondiabetic than in diabetic patients (38% vs 16%, P =.003).¹⁶ Shacham et al.¹⁷ in 2015 also found that admission hyperglycemia was an independent risk factor for the development of acute kidney injury (AKI) among nondiabetic STEMI patients undergoing primary PCI.  He studied 1,065 nondiabetic STEMI patients undergoing primary PCI. Patients were stratified according to admission glucose levels into normal (<140 mg/dl), mild (140–200 mg/dl), and severe (>200 mg/dl) hyperglycemia groups. Patients with severe admission hyperglycemia had a significantly higher rate of acute kidney injury (AKI) compared to patients with no or mild hyperglycemia (20 vs. 7 and 8%, respectively; p = 0.001) and had a significantly greater serum creatinine change during hospitalization (0.17 vs. 0.09 and 0.07 mg/dl, respectively; p = 0.04). In multivariate logistic regression, severe hyperglycemia was shown to be an independent predictor of AKI (OR = 2.46, 95% CI 1.16–5.28; p = 0.018).¹⁷ Among patients with no prior history of DM, hyperglycemia may reflect previously undiagnosed diabetes, pre-existing carbohydrate intolerance, stress-related glucose intolerance, or a combination of these factors.⁶ Stress is accompanied by high levels of catecholamines such as adrenaline and cortisol. These hormones increase glycogenolysis and lipolysis and reduce insulin sensitivity, resulting in elevated glucose levels.¹⁸

Several effects of acute hyperglycemia have direct negative impact on renal function and increase renal toxicity of contrast agents. Hyperglycemia, even in absence of diabetes, leads to increased endothelin and angiotensin levels, causing intrarenal vasoconstriction increasing the medullary lactate level, reducing pH and oxygen delivery and increasing reactive oxygen species and oxidative stress.^19,20 Thus, acute hyperglycemia may exacerbate the deleterious effects of contrast agents on the kidney. Moreover, acute hyperglycemia may induce osmotic diuresis, resulting in volume depletion and dehydration and further increasing CIN risk and severity.

In the present study acute hyperglycemia was associated with statistically significant lower MBG after 1ry PCI as compared to patients without acute hyperglycemia. Acute hyperglycemia was also associated with statistically significant higher in-hospital adverse events (VT/VF, APO, cardiogenic shock and need for mechanical ventilation) and in-hospital mortality. Acute hyperglycemia is associated with several adverse effects that contribute to poor outcome in STEMI. They include increased oxidative stress, increased cytokine activation, Inflammatory response, endothelial dysfunction and impaired microcirculatory function as manifested by post-PCI no-reflow and impaired ischemic preconditioning.^4,21-25  Hyperglycemia has also been shown to have several prothrombotic effects and enhanced platelet activation with subsequent increased risk for thrombotic events.^26-29

Several studies have demonstrated that acute hyperglycemia is a powerful predictor of mortality, larger infarct size and increased risk of cardiovascular complications in myocardial infarction patients regardless of the diabetic state.^30-35 For every 18-mg/dL increase in glucose level, there is a 4% increase in mortality in nondiabetic patients presenting with myocardial infarction.³⁶ Several studies showed that hyperglycemia during acute illness is associated with greater mortality in non diabetic patients than in those with documented diabetes.^6,37-41 This might be explained by the fact that diabetic patients may have had more opportunity to adapt to a hyperglycemic milieu and therefore are less immediately affected by acute hyperglycemia than patients who are naive to elevated glucose levels. Another possibility is that hyperglycemia is marker for illness severity. Also, individuals described as non-diabetic may actually have undiagnosed diabetes that when untreated predisposes to worse outcomes.⁴²

This is a single centre study which included a relatively small number of patients. The present study did not include HBA1c evaluation which could have provided data to compare the effect of acute vs chronic hyperglycemia. Finally, being a short term study, no long term data regarding renal functions, cardiovascular complications or long term mortality could be provided, however this could be a subject for future studies.

In the present study, acute hyperglycemia, was associated with increased incidence of CIN in STEMI patients undergoing primary PCI independent of the diabetic status of the patients. Acute hyperglycemia was also associated with increased incidence of in-hospital adverse events and in-hospital mortality.

Since admission glucose level measurement is readily available for all patients presenting with STEMI, this variable could be incorporated into risk calculation models for identification of patients at risk for development of CIN after primary PCI.

None.

No financial interest or any conflict of interest exists.

1. Marenzi G, Assanelli E, Campodonico J, et al. Contrast volume during primary percutaneous coronary intervention and subsequent contrast-induced nephropathy and mortality. Ann Intern Med. 2009;150(3):170-177.
2. Persson PB, Tepel M. Contrast medium-induced nephropathy: the pathophysiology. Kidney Int Suppl. 2006;(100):S8-S10.
3. Ceriello A. Cardiovascular effects of acute hyperglycemia: pathophysiological underpinnings. Diabetes Vasc Dis Res. 2008;5(4):260-268.
4. Nakamura T, Ako J, Kadowaki T, et al. Impact of acute hyperglycemia during primary stent implantation in patients with STelevation myocardial infarction. J Cardiol. 2009;53(2):272-277.
5. Oswald GA, Yudkin JS. Hyperglycemia following acute myocardial infarction: the contribution of undiagnosed diabetes. Diabet Med. 1987;4(1):68-70.
6. Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic review. Lancet. 2000;355(9206):773-778.
7. Zeller M, Steg PG, Ravisy J, et al. Prevalence and impact of metabolic syndrome on hospital outcomes in acute myocardial infarction. Arch Intern Med. 2005;165(10):1192-1198.
8. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J. 2012;33(20):2551-2567.
9. Péquignot R, Belmin J, Chauvelier S, et al. Renal function in older hospital patients is more accurately estimated using the Cockcroft-Gault formula than the Modification Diet in Renal Disease formula. J Am Geriatr Soc. 2009;57(9):1638-1643.
10. McCullough PA, Adam A, Becker CR, et al. Epidemiology and prognostic implications of contrast induced nephropathy. Am J Cardiol. 2006;98(6A):5K-13K.
11. Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation. 1987;6(1):142-154.
12. van 't Hof AW, Liem A, Suryapranata H, et al. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade: Zwolle Myocardial Infarction Study Group. Circulation. 1998;97(23):2302-2306.
13. Stolker JM, McCullough PA, Rao S, et al. Pre-procedural Glucose levels and the risk for contrast induced acute kidney injury in patients undergoing coronary angiography. J Am Coll Cardiol. 2010;55(14):1433-1440.
14. Naruse H, Ishii J, Hashimoto T, et al. Pre-procedural glucose levels and the risk for contrast-induced acute kidney injury in patients undergoing emergency coronary intervention. Circ J. 2012;76(8):1848-1855.
15. Moriyama N, Ishihara M, Noguchi T, et al. Admission hyperglycemia is an independent predictor of acute kidney injury in patients with acute myocardial infarction. Circ J. 2014;78(6):1475-1480.
16. Moriyama N, Ishihara M, Noguchi T, et al. Acute hyperglycemia and contrast-induced nephropathy in primary percutaneous coronary intervention. Am Heart J. 2010;160(6):1170-1177.
17. Shacham Y, Gal-Oz A, Leshem-Rubinow E, et al. Admission Glucose Levels and the Risk of Acute Kidney Injury in Nondiabetic ST Segment Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention. Cardiorenal Med. 2015;5(3):191-198.
18. Mizock BA. Alterations in fuel metabolism in critical illness: hyperglycaemia. Best Pract Res Clin Endocrinol Metab. 2001;15(4):533-551.
19. Goldenberg I, Matetzky S. Nephropathy induced by contrast media: pathogenesis, risk factors and preventive strategies. CMAJ. 2005;172(11):1461-1471.
20. Deedwania P, Kosiborod M, Barrett E, et al. Hyperglycemia and acute coronary syndrome: a scientific statement from the American Heart association Diabetes Committee of the Council of Nutrition, Physical Activity and Metabolism. Circulation. 2008;117(12):1610-1619.
21. Iwakura K, Ito H, Ikushima M, et al. Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction. J Am Coll Cardiol. 2003;41(1):1-7.
22. Ishihara M, Inoue I, Kawagoe T, et al. Impact of acute hyperglycemia on left ventricular function after reperfusion therapy in patients with a first anterior wall acute myocardial infarction. Am Heart J. 2003;146(4):674-678.
23. Ishihara M, Kojima S, Sakamoto T, et al. Acute hyperglycemia is associated with adverse outcome after acute myocardial infarction in the coronary intervention era. Am Heart J. 2005;150(4):814-820.
24. Timmer JR, Ottervanger JP, de Boer MJ, et al. Hyperglycemia is an important predictor of impaired coronary flow before reperfusion therapy in ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2005;45(7):999-1002.
25. Yang Z, Laubach VE, French BA, et al. Acute hyperglycemia oxidative stress and exacerbates myocardial infarction by activating nicotinamide adenine dinucleotide phosphate oxidase during reperfusion. J Thorac Cardiovasc Surg. 2009;137(3):723-729. 
26. Undas A, Wiek I, Stêpien E, et al. Hyperglycemia is associated with enhanced thrombin formation, platelet activation, and fibrin clot resistance to lysis in patients with acute coronary syndrome. Diabetes Care. 2008;31(8):1590-1595.
27. Geisler T, Mueller K, Aichele S, et al. Impact of inflammatory state and metabolic control on responsiveness to dual antiplatelet therapy in type 2 diabetics after PCI: Prognostic relevance of residual platelet aggregability in diabetics undergoing coronary interventions. Clin Res Cardiol. 2010;99(11):743-752. 
28. Hartge M, Unger T, Kintscher U. The endothelium and vascular inflammation in diabetes. Diab Vasc Dis Res. 2007;4(2):84-88.
29. Worthley MI, Holmes AS, Willoughby SR, et al. The deleterious effects of hyperglycemia on platelet function in diabetic patients with acute coronary syndromes. Mediation by superoxide production, resolution with intensive insulin administration. J Am Coll Cardiol. 2007;49(3):304-310. 
30. Ceriello A, Giacomello R, Stel G, et al. Hyperglycemia-induced thrombin formation in diabetes. The possible role of oxidative stress. Diabetes. 1995;44(8):924-928.
31. Kawano H, Motoyama T, Hirashima O, et al. Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J Am Coll Cardiol. 1999;34(1):146-154.
32. Sakamoto T, Ogawa H, Kawano H, et al. Rapid change of platelet aggregability in acute hyperglycemia. Detection by a novel laser-light scattering method. Thromb Haemost. 2000;83(3):475-479.
33. Monteiro S, Monteiro P, Gonçalves F, et al. Hyperglycaemia at admission in acute coronary syndrome patients: prognostic value in diabetics and non-diabetics. Eur J Cardiovascular Prev Rehabil. 2010;17(2):155-159. 
34. Chen PC, Chua SK, Hung HF, et al. Admission hyperglycemia predicts poorer short- and long-term outcomes after primary percutaneous coronary intervention for ST-elevation myocardial infarction. J Diabetes Investig. 2014;5(1):80-86.
35. Buturlin K, Minha S, Rozenbaum Z, et al. Admission plasma glucose levels within the normal to mildly impaired range and the outcome of patients with acute coronary syndrome. Eur Heart J Acute Cardiovasc Care. 2016;pii:2048872616641900.
36. Stranders I, Diamant M, van Gelder RE, et al. Admission blood glucose level as risk indicator of death after myocardial infarction in patients with and without diabetes mellitus. Arch Intern Med. 2004;164(9):982-988.
37. Kosiborod M, Rathore SS, Inzucchi SE, et al. Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes. Circulation. 2005;111(23):3078-3086.
38. Falciglia M, Freyberg RW, Almenoff PL, et al. Hyperglycemia- related mortality in critically ill patients varies with admission diagnosis. Crit Care Med. 2009;37(12):3001-3009.
39. Whitcomb BW, Pradhan EK, Pittas AG, et al. Impact of admission hyperglycemia on hospital mortality in various intensive care unit populations. Crit Care Med. 2005;33(12):2772-2777.
40. Egi M, Bellomo R, Stachowski E, et al. Blood glucose concentration and outcome of critical illness: the impact of diabetes. Crit Care Med. 2008;36(8):2249-2255.
41. Kataja A, Tarvasmäki T, Lassus J, et al. The association of admission blood glucose level with the clinical picture and prognosis in cardiogenic shock - Results fromthe CardShock Study. Int J Cardiol. 2017;226:48-52.
42. Corathers SD, Falciglia M. The role of hyperglycemia in acute illness: Supporting evidence and its limitations. Nutrition. 2011;27(3):276-281.