Fluid Overload is Associated with Underestimation of Serum Creatinine in Cardiac Surgery Patients: A Retrospective Analysis

Background: Fluid overload is related to the development and prognosis of cardiac surgery-associated acute kidney injury (CSA-AKI). The study is to investigate the influence of serum creatinine (SCr) corrected by fluid balance on the prognosis of patients with cardiac surgery. Methods: A retrospective study was conducted in 1334 patients who underwent elective cardiac surgery from January 1 to December 31, 2015. Kidney Disease: Improving Global Outcomes (KDIGO) criteria for AKI were applied to identify CSA-AKI. SCr was measured every 24 hours during ICU period and was accordingly adjusted for cumulative fluid balance. Change in SCr, defined as ∆Crea, was determined by difference between before and after adjustment for cumulative fluid balance. All patients were divided as three groups: underestimation group (∆Crea ≥ P 75 ), normal group (P 25 < ∆Crea < P 75 ) and overestimation group (∆Crea ≤ P 25 ). Results: The incidence of AKI increased from 29.5% to 31.8% after adjustment for fluid balance. Patients in underestimation group showed prolonged length of ICU stay compared with normal group and overestimation group (3.2[1.0-3.0] vs 2.1[1.0-3.0] d, P < 0.001; 3.2[1.0-3.0] vs 2.3[1.0-3.0] d, P < 0.001). Length of hospital stay and mechanical ventilation dependent days in underestimation group were significantly longer than normal group ( P < 0.001). Multivariate analysis showed age, baseline SCr and left ventricular ejection fraction were independently associated with underestimation of creatinine. Conclusions: Cumulative fluid balance after cardiac surgery disturbs accurate measurement of serum creatinine. Patients with underestimation of SCr were associated with poor prognosis.

Fluid overload can dilute serum creatinine level, which may induce delayed diagnosis of AKI and incorrect estimation of glomerular filtration rate (GFR) [15]. Therefore, aim of our study is to investigate the influence of discrepancy of serum creatinine on the prognosis of patients with cardiac surgery, and moreover, to explore underlying risk factors for underestimation of serum creatinine.

Patients
Patients who underwent cardiac surgery between January 1 and December 31, 2015 at the Department of Cardiovascular Surgery, Zhongshan Hospital, Fudan University were consecutively included in our study. Inclusion criteria were adult patients (≥ 18 years) who received elective cardiac surgery with or without cardiopulmonary bypass (CPB). Exclusion criteria were patients who had preexisting renal dysfunction requiring renal replacement therapy or had a baseline creatinine ≥ 4 mg/dl; patients who died within 24 hours after surgery as well as patients who received cardiac transplant or aortic aneurysm surgery. The Institutional Ethics Committee of the Zhongshan Hospital (B2018-175) granted permission for data collection and informed consent was waived due to the retrospective design of the study.

Data collection
Acute Physiology and Chronic Health Evaluation II (APACHE II) score was used to assess severity of illness at intensive care unit (ICU) admission [16]. Intraoperative parameters, such as CPB and crossclamp duration, type of surgery and ultrafiltration during extracorporeal circulation were recorded as well. Fluid input and output were obtained at least 24 hours since ICU admission or until discharge from the ICU, whichever occurred first. Insensitive loss of fluid was not taken into account in our study.

Definitions
Kidney Disease: Improving Global Outcomes (KDIGO) definition was utilized to identify cardiac surgery-associated acute kidney injury (CSA-AKI) [17]. The dilutional effect on the value of serum creatinine used to diagnose and staging AKI according to the KDIGO criteria was assessed.
Cumulative fluid balance was calculated based on total fluid input and output in every 24 hours.
Patients' admission weights were utilized to estimate baseline total body water (TBW). TBW = 60% of baseline weight in kilogram at admission [15].
Baseline serum creatinine was obtained immediately prior to surgery. Maximum serum creatinine was the highest value within 48 hours after cardiac surgery. During the postoperative ICU period, serum creatinine was measured at least once every 24 hours. The adjusted serum creatinine was calculated using formula utilized in previous studies [11,15,18]. Adjusted creatinine = serum creatinine × [1 + (cumulative fluid balance in L/admission weight in kg × 0.6)]. The difference of adjusted and measured serum creatinine was defined as ∆Crea.

Groups
Given that the normal distribution of ∆Crea ( Fig. 1), patients were divided as three groups: underestimation group (∆Crea ≥ P 75 ), normal group (P 25 < ∆Crea < P 75 ) and overestimation group (∆Crea ≤ P 25 ). P 25 and P 75 are used to indicate the 25 th and the 75 th percentile value of the ∆Crea, respectively. The primary outcome is in-hospital mortality rate and its relationship to the ∆Crea. The secondary outcome is length of ICU stay, total length of hospital stays as well as mechanical ventilation dependent days across these groups.

Statistical analysis
Continuous variables were expressed as means (standard deviations) or medians (interquartile range, IQR) and comparisons across three groups were made using analysis of variance (ANOVA) for normally distributed variables, Kruskal-Wallis test for non-normally distributed variables. Categorical variables were expressed as counts with proportions and compared using chi-square test or Fisher's exact test where appropriate. Difference in recognition of AKI before and after adjustment for cumulative fluid balance was evaluated with McNemar's test. Consistency of AKI diagnosis and staging were assessed in Cohen's weighted kappa coefficient. Univariate analysis was performed regarding underestimation of serum creatinine as an outcome variable. Risk factors of significance in univariate analysis were further included in multivariate analysis to confirm independent risk factors for underestimation of serum creatinine. A two-sided p value of < 0.05 was considered to be statistically significant. All analyses were performed using SPSS 11.0 software (ver. 18.0, SPSS Inc.,

Basic characteristics
A total of 1334 patients (776 men) with a mean age of 56 years (range, 18 to 82) were investigated.
Patients were divided into three groups based on ∆Crea level (Table 1). More patients had diabetes mellitus, hypertension, previous contrast exposure, surgery without CPB in underestimation group.
Man sex, weight, and history of chronic kidney disease, acute coronary syndrome as well as stroke were similar across ∆Crea groups. Differences were noted across groups with respect to age, left ventricular ejection fraction, baseline creatinine, APACHE II score, CPB and cross-clamp duration. 2. Incidence of CSA-AKI before and after adjustment The incidence of AKI based on the KDIGO criteria was 29.5% (with 24.4%, 3.0% and 2.1% in AKI stage 1-3, respectively). The in-hospital mortality rate was 1.05% (14/1334) and incidence of requirement for continuous renal replacement therapy (CRRT) during 48 hours after ICU admission was 0.37% (n = 5). After adjustment for cumulative fluid balance, the incidence of AKI elevated to 31.8% (increased from 24.4 to 26.5% in stage 1, decreased from 3.0 to 2.8% in stage 2 and increased from 2.1 to 2.5% in stage 3 respectively). AKI stage only increased by one stage in the 3 groups after adjustment for cumulative fluid balance. An increase was found in only 3.7% of those originally in stage 0, 0.4% in those originally in stage 1 and 0.5% in those originally in stage 2. The percentage of agreement for AKI diagnosis was 94.9% with a kappa of 0.86 (95% confidence interval [CI], 0.83-0.89), whereas percentage of agreement for AKI staging was 93.8% with a kappa of 0.86 (95% CI, 0.83-0.89) after adjustment for cumulative fluid balance ( Table 2).   (Table 3). There were no statistical difference in the in-hospital mortality rate and the incidence of CRRT across these groups.

Risk factors associated with underestimation of serum creatinine
Multivariate analysis indicated that factors independently associated with underestimation of serum creatinine due to the cumulative fluid balance were older age (P = 0.035), higher baseline serum creatinine (P < 0.001), lower left ventricular ejection fraction (P = 0.001), and extent of cumulative fluid balance (P < 0.001) during ICU stay after cardiac surgery (Table 4).

Discussion
In this retrospective cohort study, we found that when after adjusting serum creatinine for the cumulative fluid balance, more patients met KDIGO criteria for CSA-AKI. Patients with underestimation of serum creatinine had worse outcomes in terms of length of ICU stay, total length of hospital stay and mechanical ventilation dependent days, but not in the incidence of CRRT and in-hospital mortality rate.
Since minimal increase of serum creatinine was associated with adverse outcomes in patients within the ICU setting, precise recognition and accurate assessment of AKI may contribute to prevention and early intervention of reversible risk factors [19][20][21][22]. Serum creatinine may normally be influenced by several factors, including renal creatinine clearance or creatinine formation or both [23]. Importantly, serum creatinine level also can be affected by dilution effect of fluid resuscitation, which is frequently occurring in critically ill patients [22,24]. Our results indicate that cumulative fluid balance in patients with cardiac surgery somewhat underestimate the diagnosis and staging of AKI, which is in accordance with previous studies [11,15].
Post hoc analysis of Fluids and Catheters Treatment study illustrated that incidence of AKI with acute respiratory distress syndrome was greater in those managed with liberal fluid protocol than conservative fluid protocol after adjustment for fluid balance [11]. Moreover, mortality rate of these patients was similar to patients diagnosed with AKI before and after adjustment for fluid balance.

Macedo et al. conducted analysis in patients underwent nephrology consultation for AKI in the ICU,
which showed dilution effect of fluid overload on serum creatinine may delay diagnosis time for AKI [15]. Study focusing on cardiac surgery patients also demonstrated that patients with AKI only after adjustment for fluid balance had intermediate outcomes between non-AKI and classical AKI patients [12]. Our study demonstrated that patients with underestimation of serum creatinine had prolonged mechanical ventilation dependent days, longer length of ICU stay as well as longer length of hospital stay.
Multivariate analysis of our study also found that after adjustment for relevant risk factors, patients with older age, lower left ventricular ejection fraction, higher baseline serum creatinine and severe extent of cumulative fluid balance after cardiac surgery were independently associated with underestimation of serum creatinine. Thus, to reduce underestimation of serum creatinine along with subsequent prediction of poor prognosis, risk factors including age, baseline cardiac function as well as baseline kidney function should be taken into account during fluid administration in patients undergoing cardiac surgery. There are several limitations in our study. First, as a single center study, regardless of a large cohort of cardiac surgery patients, inherent bias of study design still remains to concern. Second, types of fluid given to patients during perioperative period were not included in the analysis owing to lacking of detailed record for fluid profile. Third, cause of fluid administration was not easily distinguished from our database. Excess fluid administration may be in an effort to manage low cardiac output, and fluid accumulation may be secondary to inflammatory response. Both low cardiac output and inflammation might be responsible for the development of AKI. Last, insensitive fluid loss during study period was not taken into account, which may influence accurate measurement of fluid balance, especially when patients were incubated during ICU period.
Regardless of these limitations, our study highlights dilution effect of cumulative fluid balance on serum creatinine and further illustrates associated outcomes in cardiac surgery patients, which may benefit physicians to recognize mild AKI via adjustment for cumulative fluid balance. Strikingly, our study identified for the first time the risk factors including age, baseline cardiac function, and preoperative kidney function were independently associated with the underestimation of serum creatinine, which could contribute to screening patients at high risk for misinterpretation of postoperative serum creatinine. However, much more advanced studies should be designed to clear the underlying association between concealed mild AKI and actual change of renal function, such as using combination of serum creatinine and kidney injury biomarkers to timely detect deterioration of kidney function after cardiac surgery [25,26].

Ethics approval and consent to participate
The study was approved by the Institutional Ethics Committee of Zhongshan Hospital, Fudan University, Shanghai, China (B2018-175). The need for informed consents were waived by the Institutional Ethics Committee because this was a retrospective analysis of data collected prospectively with no breach of privacy or anonymity.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interest
The authors declare that they have no competing interests.

Funding
This study was supported by the research grants from the Science and Technology Commission of