Impact of renal function on patients with acute coronary syndromes: 15,593 patient-years study

Abstract Introduction Coexistence of chronic kidney disease (CKD) in the case of acute coronary syndromes (ACS) significantly worsens the outcomes. Aim The aim of our study was to assess renal function impact on mortality among patients with ACS. Materials and methods The study was based on records of 21,985 patients hospitalized in the Medical University of Bialystok in 2009–2015. Inclusion criteria were ACS. Exclusion criteria were: death within 24 h of admission, eGFR <15 ml/min/1.73 m2, hemodialysis. Mean observation time was 2296 days. Results Criteria were met by 2213 patients. CKD occurred in 24.1% (N = 533) and more often affected those with NSTEMI (26.2 (337) vs. 21.2 (196), p = .006). STEMI patients had higher incidence of post-contrast acute kidney injury (PC-AKI) (5 (46) vs. 4.1 (53), p < .001). During the study, 705 people died (31.9%), more often with NSTEMI (33.2% (428) vs. 29.95% (277), p < .001). However, from a group of patients suffering from PC-AKI 57.6% died. The risk of PC-AKI increased with creatinine concentration (RR: 2.990, 95%CI: 1.567–5.721, p < .001), occurrence of diabetes mellitus (RR: 2.143, 95%CI: 1.029–4.463, p = .042), atrial fibrillation (RR: 2.289, 95%CI: 1.056–4.959, p = .036). Risk of death was greater with an increase in postprocedural creatinine concentration (RR: 2.254, 95%CI: 1.481–3.424, p < .001). Conclusion PC-AKI is a major complication in patients with ACS, occurs more frequently in STEMI and may be a prognostic marker of long-term mortality in patients undergoing percutaneous coronary intervention (PCI). More attention should be given to the prevention and diagnosis of PC-AKI but necessary PCI should not be withheld in fear of PC-AKI.


Background
Cardiovascular diseases are the leading cause of mortality among the Polish population. These are responsible for 46% of deathsit is almost twice as much as deaths caused by cancer (27%) [1]. Kidney disease affects cardiac function and can change the course and prognosis of patients with acute coronary syndromes (ACS) [2].
A Polish study on the assessment of the incidence of chronic kidney disease (CKD) among the Polish population claims that CKD affects about 5.8%, where in the case of seniors the percentage is 26.9%. Some studies suggest that CKD is the greatest risk factor for cardiovascular diseases occurrence [3][4][5].
CKD is highly prevalent worldwide and is associated with an increased risk for adverse outcomes in patients hospitalized due to ACS, the co-occurrence of these two diseases increases the risk of death [6].
The gold standard of treatment for patients with ACS is percutaneous coronary intervention (PCI). Many patients after PCI experience a decrease in GFR, which is a certain group manifests itself as post-contrast acute kidney injury (PC-AKI).
Data on the impact of post-procedural eGFR decline on mortality in patients with ACS are still limitedit is known that this condition is associated with more adverse outcomes [7]. Therefore, in our study, we aimed to investigate which factors predispose to contrast-induced acute kidney injury and how it affects mortality among patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI).

Patients and methods
The study was conducted at the Clinical Hospital of Medical University of Bialystok. Based on the medical records of 2258 men and women hospitalized due to ACSs in 2009 À 2015.
The demographic, clinical, and biochemical data of the patients were evaluated. The diagnosis of STEMI and NSTEMI was made by physicians based on the symptoms, level of biochemical markers of myocardial necrosis, and electrocardiographic results.
All patients underwent coronary angiography. During all procedures, an iodine-containing nonionic radiocontrast agent was used. All patients had the same strategy for the prevention of radiocontrast agent -1000 mL of intravenous hydration with 0.9% NaCl.
CKD-EPI eGFR and creatinine levels were assessed on admission and 48 h after angiography, based on age, gender, race, and creatinine concentration [8]. For the purpose of this study, PC-AKI was defined as an absolute increase of serum creatinine !0.5 mg/dL or relative increase !25% from the baseline value within the first 48 h of intervention. Currently, newer, more strict criteria are available [9], however, given that the study covers patients hospitalized between 2009 and 2015, thus the end of the study took place before the new guidelines appeared, we decided to use values current for this period. Around 1.19% of the data were missing during the study period, and these data were excluded from the analysis.
The study protocol was approved by the ethics committees of the Medical University of Bialystok (R-1-002/ 18/2019).
In this group, the main causes of death were cardiovascular diseases 93.3% (N ¼ 42) of which 51.1% of death was reported in 24 h of admission (N ¼ 23).

Long-term observation
The data concerning the cause of deaths that were recorded on April 1, 2019, were obtained from the Statistical Office in Olsztyn, Poland. The records included the causes of deaths that were classified according to codes in the International Classification of Diseases -10th Revision (ICD-10).
The mean follow-up period from the onset to the death was 1319 (SD ¼ 1070), median -1230 days. The complete follow-up duration consisted of 2296 days (SD ¼ 1081), median -2359.

Statistical analysis
The distribution of variables was evaluated using the Kolmogorov-Smirnov test. The two-tailed t-test and Mann-Whitney U test were used for comparative analysis. Spearman's rank correlation test was applied to evaluate the relationships between the levels of postprocedural decrease of eGFR and biochemical parameters.
The effects of clinical and biochemical factors on death were evaluated by multivariable logistic regression backward stepwise Wald method.

Results
A total of 2213 patients were included into the final analysis -1288 with NSTEMI and 925 with STEMI. The average age was 65.8 years (SD ¼ 12.2) and men were in the majority (65.2%, N ¼ 1442) (Figure 1).
Multivariable regression analysis showed that the risk of death in both STEMI and NSTEMI groups was greater with an increase in postprocedural creatinine concentration (for an increase of 1 mg/dl risk ratio was:

Discussion
In recent years, the epidemiology of ACSs has changed in Poland and Europe. Non-ST-segment elevation myocardial infarction starts to play a dominant role, which is in line with our study [10,11]. Short-term mortality is higher in the STEMI group, however, in the case of long-term follow-up, the death rate for NSTEMI becomes twice as high in comparison to STEMI [10,12]. These data are reflected in our analysis. Differences in prognosis over time result from different characteristics of patients, people predisposed to NSTEMI are usually older and have more coexisting diseases, especially diabetes and renal failure.
In this investigation, CKD occurred in one out of four people and more often affected those with NSTEMI. Patients with CKD had worse outcomes regardless of the type of ACS. These results can be found in previous studies, CKD of any degree is a potential and independent risk factor for adverse outcomes. [13,14]. Population with CKD had more often comorbidities, such as hypertension, diabetes mellitus, atrial fibrillation, and advanced age which is mostly traditional risk factors for cardiovascular diseases. CKD is also associated with a high burden of cardiovascular diseases, especially coronary artery disease which has an impact on poorer long-and short-term outcomes after ACS [15][16][17]. These findings are reflected in current guidelines. Individuals with CKD are considered as a group of high risk for cardiovascular diseases and other adverse outcomes which supports calls for more intensive intervention in patients with CKD to prevent them. Therapeutic strategies that have been proved to prevent cardiovascular events in patients with CKD include aggressive blood pressure control, statins, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers [18]. An additional burden, especially in the group of CKD patients, was the occurrence of PC-AKI. Contrastinduced acute kidney injury occurred in 99 patients, in every 20th patient with STEMI, however, in the group of patients with CKD history almost 10 percent of the patients were affected. Contrast nephropathy is a common complication, however, the risk of death associated with it is lower than the risk of untreated infarction. PCI is the gold standard procedure [19]. Its effectiveness in reducing mortality is greater than other reperfusion therapy strategies. There are several    methods of the prevention of acute renal injury after the administration of contrast, which should be used in high-risk patients (the population with CKD) [20]. However, scientific work so far has focused mainly on the risk of infarction in CKD patients or on the influence of GFR on infarct severity [21,22]. This research allows us to estimate the prognosis in post-infarction patients, after the performed intervention and assess which patients require particular attention. This is a useful marker while considering the whole population with STEMI or NSTEMI infarction. The studies performed so far report that PC-AKI has a strong impact on an increased risk for adverse clinical outcomes in patients with ACS and increased mortality in post-procedural patients. Our study confirms this theory. During the analysis, it was noted that patients with contrast nephropathy have significantly higher mortality rates [7,[23][24][25][26][27][28].
Patients who are scheduled to have a contrastenhanced diagnostic or interventional procedure should be evaluated for risk factors of PC-AKI. Previous studies report about various initiators increasing the risk of complications, where the most important is preexisting CKD. Our analysis shows that the risk of PC-AKI is twice as high in patients with diabetes and atrial fibrillation and increases also as the baseline creatinine concentration rises.
One of the most interesting results of our study is a significant role of risk factors, which seems to be underestimated. It is well known that age, diabetes mellitus, prior ACS, time from door to balloon, tachycardia, hypotension, and cardiogenic shock are independent predictors of poor prognosis in patients with ACS. In addition, Shacham et al. have shown that the presence of severe hyperglycemia on admission without previously diagnosed diabetes was an independent risk factor for the development of AKI among STEMI patients undergoing primary PCI [29]. However, in our study, the main prognostic factor was post-procedural creatinine concentration. An increase in post-procedural creatinine concentration of 1 mg/dl in long-term observation resulted in 2.2 times higher death risk ratio. An important impact of renal function was observed in other results. The mortality of patients with contrast-induced acute kidney injury was more than two times higher in the group of CKD in comparison to the rest of the population. In the literature, the impact of CKD on long-term mortality of patients with ACSs was reported   with odds ratios between 1.66 and 2.8 [30,31]. In our study, PC-AKI was observed in ninety-nine patients (4.47%). Although the occurrence rate of PC-AKI was higher in the recent studies (11.2 À 16.1%), similarly to our results it was more common in patients diagnosed with STEMI [32][33][34].
The reason for taking PC-AKI as a strong predictor of death is not only the observation that renal function of half of PC-AKI patients did not return to the baseline concentration but also in almost half of the group it was leading to CKD [35,36]. On the other hand, patients with PC-AKI have more severe coronary artery disease, a higher burden of traditional coronary risk factors, and complications such as diabetes mellitus, hypertension, left ventricular hypertrophy, dyslipidemia, atrial fibrillation, and congestive heart failure, what had an impact on the long-term mortality.
Our results suggest that PC-AKI has a negative impact on outcomes of patients with ACS treated with invasive procedures. More attention should be paid to the prevention and diagnosis of PC-AKI. Nevertheless, necessary PCIs should not be withheld in the fear of PC-AKI.

Limitations
Our study had several limitations. Firstly, it was a retrospective, single-center study, but covering a large population. The second limitation is a high percentage of garbage codes in mortality statistics (4-30%). Thirdly, the level of creatinine before ACS and in long-term follow-up is not included in our study. Baseline creatinine values may already reflect impairment from hemodynamic changes in the setting of acute myocardial infarction. Control assessment of creatinine level would let us assess the impact of developing CKD in PC-AKI and non-PC-AKI patients and how the concentration of creatinine returns to baseline levels.
Finally, we might have potentially underestimated the real incidence of PC-AKI, as our protocol only recommended measurement of creatinine level for 2 days after admission. In addition, a potential underestimation of the phenomenon of PC-AKI may be due to the use of historical definition and creatinine level control at 48 h instead of the commonly accepted 72-h delay. Thus, we might have missed later rises in serum creatinine.

Conclusions
Chronic kidney disease affects mostly the population with NSTEMI infarction. Contrast-induced acute kidney disease is a major complication in patients with ACS and occurs more frequently in the STEMI population. The risk of CI-AKI is increased in patients with preprocedural renal insufficiency. CI-AKI may be a prognostic marker of long-term mortality in ACS patients undergoing PCI.
More attention should be paid to the prevention and diagnosis of CI-AKI but necessary PCIs should not be withheld in fear of CI-AKI.