Nonlinear relationship between blood glucose and 30-day mortality in critical patients with acute kidney injury: A retrospective cohort study

Results: We identifi ed 18,703 consecutive individuals with AKI. The average age of the participants was 66.8 ± 16.0 years, and about 42.7% of them were female. The overall 30-day mortality was 16.9%. Through the multivariate COX regression model and smooth curve fi tting, we observed that the correlation between blood glucose and 30-day mortality is nonlinear. An infl ection point was found at about 5.93 mmol/L. On the left side of infl ection point, the eff ect size was 0.81 (HR: 0.81, 95% CI 0.74-0.89, p < 0.001). On the right side of infl ection point, the eff ect size was 1.02 (HR: 1.02,95% CI 1.01-1.03, p < 0.001).


Introduction
Acute kidney injury (AKI) is or health problem affecting millions of people worldwide, leading to decreased survival, underlying chronic kidney disease (CKD) progression, and new CKD onset occasionally [1]. Effective preventa tive and therapeutic treatments remain to be produced [2].
Previous study showed an increase in the blood glucose levels beyond normal values is associated with an increase in the incidence of AKI [3,4]. However, researches have known far less about the relationship between blood glucose and mortality in critical patients with AKI. In addition, our previous study indicated an antihyperglycemic agent, metformin may be associated with reduced risk-adjusted mortality in patients with AKI [5]. Therefore, we conducted a retrospective cohort study to determine the association between blood glucose and mortality in critical patients with AKI.

Participants and methods
We conducted a retrospective cohort study and enrolled critical patients with AKI from the Medical Information Mart for Intensive Care (MIMIC)-III (version 1.4). MIMIC-III is a real-world clinical database containing more than 60,000 intensive care unit (ICU) admissions at Beth Israel Deaconess Medical Center between 2001 and 2012 [6]. Qilin Yang, one of the authors, obtained approval to use the database (certi ication number 7634793) [5]. All reporting followed the Strengthening the Reporting of Observational Studies in Epidemiology guidelines [7].

Study population
Adult patients (older than 18 years) in the MIMIC-III who fullfed the de inition of AKI within 48 hours after ICU admission were eligible for inclusion. AKI was de ined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. KDIGO criteria include [8], increase in serum creatinine (SCr) ≥ 1.5 times baseline within the prior 7 days, ≥ 0.3 mg/dL increase in SCr within 48 h, or urine volume < 0.5 mL/kg/h for at least 6 h. The lowest of the SCr values available within 7 days before admission was used as the baseline SCr [9]. When SCr prior to admission was not available, the irst SCr measured on ICU admission was used as the baseline SCr [10]. For patients with recurrent ICU admissions, only the irst ICU admission was considered.

Variable extraction
Blood glucose: We obtained baseline blood glucose as the irst glucose within 24 h after ICU admission in MIMIC-III database.
Covariates: We included the following variables based on published literature and our clinical experience: demographic characteristics, and baseline heart rate, mean arterial pressure (MAP), SPO 2 , white blood cell (WBC) count, hemoglobin, platelet count, serum creatinine (SCr), simpli ied acute physiology score (SAPS) II score, ventilator use in irst day, vasopressor use in irst day, renal replacement therapy (RRT) use in irst day, and comorbidities (congestive heart failure liver disease, coronary heart disease stroke, malignancy, diabetes). Vasopressors included norepinephrine, epinephrine, phenylephrine, vasopressin, dopamine, dobutamine, and isoprenaline.

Outcome:
The outcome was 30-day mortality.

Statistical analysis
Descriptive analysis was performed for all patients. Categorical variables were expressed as numbers and percentages. Continuous variables were expressed as mean and standard deviation (SD) for normal distributions or median and interquartile range for skewed distributions. We used the chi-square test, one-way ANOVA, and Kruskal-Wallis test for the comparison of categorical, normally distributed, and non-normally distributed continuous variables, respectively.
Multivariable Cox regression analyses and smooth curve itting were adopted to assess the independent association between blood glucose and 30-day mortality. To examine the nonlinear association between blood glucose levels and 30-day mortality, we further applied a two-piecewise linear regression model using a smoothing curve. We conducted a loglikelihood ratio test comparing the one-line linear regression model with the two-piecewise linear model. Survival curves were plotted by Kaplan-Meier and log-rank analyses.
All the analyses were performed with the statistical software packages R 3.3.2 (http://www.r-project.org, The R Foundation) and Free Statistics software versions 1.1. A two-tailed test was performed and p < 0.05 was considered statistically signi icant.

Baseline characteristics of participants
We identi ied 18,703 consecutive individuals with AKI according to the KDIGO de inition ( Figure 1). Baseline characteristics of selected participants according to quartiles of blood glucose are shown in table 1. In general, the average age of the participants was 66.8 ± 16.0 years old, and about 42.7 of them were female. The overall 30-day mortality was 16.9%.

Relationship between the blood glucose and 30-day mortality in AKI patients
Kaplan-Meier curve showed there was lower mortality in patients in Q2 (6.11-7.44 mmol/L) and Q3 (7.44-9.28 mmol/L) groups (Log-rank test: p < 0.0001, Figure 2). The results of univariate and multivariate COX regression model are shown in table 2. In fully adjusted model (Adjusted for all covariates in table 1), a 1 mmol/L increment in blood glucose was associated with 1% higher 28-day mortality (HR = 1.01; 95% CI, 1.01, 1.02, p = 0.012, Table 2). For the purpose of sensitivity analysis, we also handled blood glucose as a categorical variable (quartiles) and found p for trend was 0.122, Table 2).

The nonlinear relationship between blood glucose and 30-day mortality
Through the multivariate COX regression model and smooth curve itting, we observed that the correlation between blood glucose and 30-day mortality is nonlinear ( Figure 3). Data were it to a piecewise multivariate COX regression model to its two different slopes. In our study, the p for log-likelihood ratio test was less than 0.001 (Table 3), we thus used two-piecewise model to itting the link between blood glucose and 30-day mortality. We found an in lection point at about 5.93 mmol/L. On the left side of in lection point, the effect size was 0.81 (HR: 0.81, 95% CI 0.74-0.89, p < 0.001) On the right side of in lection point, the effect size was 1.02 (HR: 1.02,95% CI 1.01-1.03, p < 0.001).

Discussion
In this observational retrospective cohort study, we examined the optimal of blood glucose associated with 30-day mortality in critical patients with AKI using MIMC-III database. We found nonlinear association between blood glucose with 30-day mortality in these patients. The correlations between blood glucose and 30-day mortality of critical patients with AKI were totally different below and above the in lection point which was 5.93 mmol/L. Blood glucose, as assessed at baseline, was negatively associated below the 5.93 mmol/L, and it was positively associated with 30-day mortality of AKI patients above the 5.93 mmol/L. The optimal of blood glucose associated with the lowest risk of 30-day mortality was around 5.93 mmol/L.
The explanations for the nonlinear relationship between glucose level and mortality in critical patients with AKI have not been well established. Hypoglycemia increases risk of death in critically ill patients [11]. Hypoglycemia may induce sympathetic adrenal activation, abnormal cardiac repolarization, thrombosis,   in lammation and vasoconstriction, which may further lead to adverse reactions [12,13]. Slightly elevated blood glucose may be an evolutionarily conserver adaptive strategy in nature that allows the host to survive during illness [14]. However, excessively high blood glucose may lead to the increases the in lammation reaction and cause immunosuppression, endothelial cell dysfunction, nervous system injury, oxidative stress [15,16]. Clinical studies also suggested hyperglycemia is strongly associated with increased coronary intervention associated AKI and in-hospital mortality [4].
There are exceedingly few published data on blood glucose and mortality in AKI. However, several previous studies have demonstrated the nonlinear relationship between fasting glucose level and adverse outcomes, such as the risk of incident atherosclerotic cardiovascular diseases [17] and all-cause mortality by age in diabetes [18]. Consistent with our study, several studies found, the optimal range of blood glucose levels associated with the lowest risk of all-cause mortality was 5.27-6.94 mmol/L [19,20]. In critical patients, among patients with sepsis, based on a meta-analysis, there was a nonlinear relationship between blood glucose with blood glucose level at 8.06 to 8.61 mmol/L corresponding to lowest mortality. Since our study enrolled only AKI patients, the optimal blood glucose associated with the lowest mortality (around 5.93 mmol/L) could be lower than that reported in previous studies in sepsis. Our study further extended this nonlinear relationship in critical patients with AKI.
Our research has the following shortcomings and needs attention: First, residual confounders such as reason of AKI, smoking status and alcohol use potentially exist, as with all retrospective analyses. We adjusted for all possible confounders as we can. Second, our indings can be only generalized to critical patients with AKI only, and the correlation of glucose on mortality may be different in other patients. Third, previous glycemic control/baseline glucose and Glycosylated haemoglobin prior to ICU admission were not in our analysis, however we adjusted history of diabetes. Finally, the causes of death were not recorded in the MIMIC-III database, we could not conduct a competing risk analysis.

Conclusion
In summary, our study suggested that, among patients with AKI, there was a nonlinear relationship between blood glucose and mortality in patients with AKI. The optimal of blood glucose associated with the lowest risk of 30-day mortality was around 5.93 mmol/L.

Availability of data and materials
Data in the article can be obtained from the MIMIC-III database (https://mimic.physionet.org/)

Funding
This article is fully funded by <<Guangdong Natural Science Foundation>> with grant number: << 2017B030311019>>.

Authors' contributions
Qi-lin Yang and Weichao Huang conducted data analysis and wrote the manuscript. Xiaomei Zeng conducted data analysis. Jie-zhao Zheng conducted data clean. Wei-xiao Chen conducted data collection and data interpretation. Deliang Wen designed the study and reviewed the manuscript.
All authors read and approved the manuscript for publication.