Introduction
Acute kidney injury (AKI) is a frequent complication in patients with acute myocardial infarction (AMI) and remains a leading contributor to the poor prognosis even after optimal medication and revascularization with percutaneous coronary intervention (PCI) [
1‐
4]. Among various risk factors for AKI, both diabetes mellitus (DM) and stress hyperglycemia have been emphasized for its good discrimination for AKI and cardiovascular (CV) adverse events [
5‐
7]. Therefore, there is an urgent need to understand the critical role of elevated glycemia in AKI development and to establish an ideal biomarker for AKI prediction in AMI patients.
Elevated glycemia at admission has been used to identify stress hyperglycemia, however, its values are affected by both acute stress condition and chronic glycemic control, and a high value of admission blood glucose (ABG) doesn’t necessarily indicate an acute glucose-level rise in response to AMI, especially in DM patients with chronic glycemic elevation [
8]. Previous studies also proved that the relationship between admission glycemia and the risk of AKI was prominent among nondiabetic patients, however, it was no longer significant in patients with DM [
9,
10]. These findings suggest that a relative increase in glycemia may have more clinical implications in early recognition and prevention of AKI in AMI patients with DM. Recently, a novel index of stress hyperglycemia (stress hyperglycemia ratio, SHR) was proposed and defined as ABG divided by the estimated average glucose (eAG) [
8], while eAG was derived from the glycated hemoglobin (HbA
1c) [
11]. Following its introduction, the performance of SHR has been developed and validated in AMI patients [
12,
13], showing a superior discrimination for in-hospital morbidity and mortality than admission glycemia alone [
14,
15]. Yet, data regarding the predictive value of SHR for AKI in AMI patients with DM are scarce. In the present study, we investigated whether the combined evaluation of acute and chronic glycemic levels as expressed by SHR could predict AKI in hospitalized AMI patients with DM and whether the predictive power of this ratio might be better than admission glycemia alone.
Discussion
In the present study, we found that SHR, instead of ABG, was significantly associated with the risk of AKI and adverse CV events in AMI patients with DM, even after adjustment for major confounders. The predictive value of SHR for AKI was better than admission glycemia alone, indicating that the combined evaluation of acute and chronic glycemic levels enables more accurate prediction of AKI after an AMI, especially in patients with DM.
The concept of stress hyperglycemia emphasizes a relative acute increase of glycemia in response to stress reaction or critical illness [
26]. Recently, stress hyperglycemia is increasingly being seen in AMI patients with or without DM and has been recognized as one of the critical risk factors for AKI and adverse complications [
27]. However, the association between elevated glycemia at admission and risk of AKI was more prominent in non-DM patients than in DM after AMI [
28]. Several studies proved that admission glycemia (ABG) could predict AKI and CV events in non-DM [
29,
30], but it was no longer a significant predictor of prognosis in DM [
9,
10]. Similarly, we found that elevated ABG was not a risk factor for AKI and CV events in AMI patients with DM. The explanation might be that a single ABG value did not take the average glycemic level into account. Many diabetic patients had achieved a good glycemic control after receiving an optimal glucose-lowering treatment while others had not. Thus, a high level of ABG did not necessarily reflect a genuine glycemic rise in response to AMI, especially in diabetic patients with chronically elevated glycemic levels, and the performance of ABG for AKI prediction might be attenuated in DM. To address this issue, a more refined marker is needed to identify the true stress hyperglycemia and to facilitate the discrimination of AKI.
The index SHR, also known as acute-to-chronic glycemic ratio, was first introduced in 2015 through quantifying the magnitude of a relative glycemic rise from chronic glycemia of the past 2–3 months [
8]. As proposed by Roberts, SHR could identify true stress hyperglycemia and was a better biomarker of critical illness than admission glycemia in patients across the whole glycemic spectrum [
8]. Since then, several studies have confirmed the prognostic power of SHR in AMI patients and in all-comers undergoing PCI [
12‐
14]. Our recent study also proved that SHR was more accurate in predicting in-hospital morbidity and mortality than admission glycemia alone among diabetic STEMI patients after PCI [
15]. In line with previous studies, we found that SHR was more associated with the risk of AKI than ABG, and its level was also correlated with the AKI severity. Stress hyperglycemia defined by SHR ≥ 1.23 was a strong predictor of AKI in overall and in subgroups of patients. These data suggest that this novel biomarker may provide more prognostic information on AKI in AMI patients with DM.
A large number of studies have identified various risk factors of AKI occurrence in AMI, including advanced age, hypertension, DM, CKD, anemia, severe Killip class, tachycardia at presentation, longer reperfusion time, decreased serum albumin and more contrast used [
31‐
33]. In the present study, we found that higher SHR and baseline cardiorenal dysfunction (reduced eGFR, decreased LVEF and increased NT-proBNP) were independent predictors of AKI. A combined model of SHR, LVEF, NT-proBNP, and eGFR showed a satisfactory discrimination for AKI, which may assist in the early detection of AKI in diabetic patients after an AMI.
A strong relationship among stress hyperglycemia, AKI occurrence and poor prognosis in patients with AMI has been identified for decades. Our cohort indicated that AMI patients with DM who had higher SHR tertiles were more likely to develop AKI, cardiogenic shock and all-cause death. The underlying mechanisms are manifold. Beyond the widely recognized hemodynamic influences of reduced cardiac output and venous congestion that contribute to hypoperfusion of the kidneys and a marked decline in renal function, an abnormal burst of neuroendocrine and inflammatory activation also accelerates the renal injury [
34,
35]. Of these, stress hyperglycemia plays a pivotal role in the AKI development followed by AMI. An acute glycemic rise can induce osmotic diuresis and thus lead to volume depletion and dehydration. Moreover, acute hyperglycemia directly enhances inflammation and oxidative stress [
36], which may further suppress the flow-mediated vasodilation and reduce renal perfusion [
37]. All these pathophysiologic changes in response to acute hyperglycemia could markedly exacerbate the deleterious effects of contrast agents, IABP, and other contributing factors on the kidneys and finally result in a poor prognosis.
In clinical practice, the dynamic measurements of Scr should be emphasized because daily Scr value and its change pattern facilitate to identify AKI at early stages and they are stronger predictors of in-hospital mortality than the initial Scr only [
38]. Meanwhile, stress hyperglycemia and AKI are both commonly seen complications after AMI. The AKI occurrence represents the confluence of cardiorenal interactions, involving the cross-talk between the failing heart and acute responses of kidneys, whereas stress hyperglycemia is implicated in hemodynamic instability, neurohormonal release and inflammatory reaction, thereby exerting detrimental effects on renal function [
35]. Due to the good performance of SHR for AKI prediction, it may be used as a bedside marker to early discriminate patients at high risks to develop AKI. Moreover, the assessment of SHR may help practitioners to tailor glucose-lowering strategies. Till now, the tight glycemic control strategies are proved to have neutral or even deleterious effects on CV outcomes in DM patients [
39‐
41]. Not only is that an intensive glucose lowering can markedly increase the risk of severe hypoglycemia, [
42] but the phenomenon of metabolic glucose memory also exists in DM, indicating that the prior glycemic control may have a sustained effect that persists even after returning to the current glycemic status [
43]. Therefore, a relative glycemic rise rather than admission glycemia alone should be more emphasized. For patients who had a high level of glycemia at admission, chronic glycemic levels still need to be considered to set the optimal target value of glucose lowering. Meanwhile, for patients whose glucose levels are below the conventional treatment threshold (11 mmol/L), SHR is useful to discriminate a real glycemia rise and thus may assist physicians to decide when to initiate glucose-lowering therapy. The prospect of the SHR would be promising for its good effectiveness and applicability. But far from claiming superiority or perfection, we should note that the predictive accuracy of this novel marker is still moderate and its performance should to be further verified by external validation.
Limitations
Some limitations should be mentioned. First, despite major clinically relevant variables were adjusted in the multivariate model and subgroup analysis was performed, the effects of nephrotoxic drugs and some other possibly residual confounding factors on AKI development were not analyzed, which may affect the outcomes. Second, similar with other studies on AKI, the time interval during measurements of serum creatinine at admission and the first 72 h was not predetermined and fixed. This may add bias to the identification of acute increase in serum creatinine. Third, this was an observational study at a single center, the sample size was limited and a definite cause-effect relationship between stress hyperglycemia and AKI cannot be established. Further multicenter and larger randomized controlled trials are needed to validate our findings, to identify more specific biomarkers of stress hyperglycemia for AKI prediction, and to investigate whether a glucose-lowering strategy targeted on SHR instead of ABG may result in a renal-protective effect in AMI patients with DM.
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