Postoperative anemia is a risk factor for acute kidney injury after open aorta and vena cava surgeries

Open aorta and vena cava surgeries are usually associated with substantial blood loss which may result in postoperative acute kidney injury (AKI). The present study is designed to investigate the prevalence, outcome and risk factors of postoperative AKI associated with open aorta and vena cava surgeries, with a focus on the role of anemia in these conditions. A retrospective review of medical records of Peking Union Medical College Hospital was conducted. Patients who underwent open aorta and vena cava surgeries during January 1, 2010 and June 30, 2014 were included in this study. The primary analysis was between patients underwent open aorta and vena cava surgeryies, with or without postoperative AKI. Multivariable logistic regression models were used to determine risk factors of postoperative AKI. The study included 79 patients (63.3% male) with a mean age of 52.5±17.3 years (range, 17–81 years). Postoperative AKI occurred in 23/79 (29.1%) of the patients. Anemia was present in 11/79 (16%) at baseline, and increased to 45/79 (52%) postoperatively. After adjustment for various risk factors, postoperative anemia (OR, 5.202; 95% CI 1.403–19.285) was independently associated with postoperative AKI. AKI is a common complication in patients who undergo open aorta and vena cava surgeries, and postoperative anemia was the most relevant predictive factor of AKI. Strategies to minimize bleeding and anemia for all patients may be advisable. Further studies are needed to assess the impact of AKI on long term outcome and to examine preventive strategies to address potentially modifiable risk factors.


Introduction
Acute kidney injury (AKI) is a prevalent and prognostically significant complication in surgical patients. Depending on the AKI definitions adopted and the population studied, AKI occurs in up to 16% -48% of surgical patients [1][2][3]. AKI after any type of surgery is independently associated with substantially worse outcomes, including higher short-term mortality, prolonged length of hospital stay, worsened long-term survival, and increased risk of end stage renal disease (ESRD) [4][5][6][7][8].
Despite advances of endograft techniques, open aorta and vena cava surgeries are still used in patients unsuitable for endovascular repair, and are associated with substantial incidence of postoperative AKI [9,10]. These procedures are usually associated with significant blood loss, which may result in hypovolemia or hypoxemia. Regionally reduced oxygen supply lead to physiologically low oxygen tensions within the renal cortex and the medulla and may cause postoperative AKI [2,3]. However, most previous researches focused on AKI after endovascular procedures which may be associated with contrast use, and the prevalence, risk factors and outcomes of AKI after open aorta and vena cava surgeries were poorly addressed in the literatures. Hence we performed an analysis in patients underwent open surgeries of major vasculatures including aorta and vena cava, to investigate the prevalence, outcome and risk factors of postoperative AKI, with a focus on the role of anemia in these conditions.

Materials and methods
This study was approved by the Institutional Review Board (IRB) of Peking Union Medical College Hospital the University (S-K048).

Database and participants
We conducted a retrospective review of the medical records of patients during September to November, 2015. The patients underwent vascular surgeries at Peking Union Medical College Hospital from January 1, 2010 to June 30, 2014. The medical records were accessed on patients who underwent vascular surgeries of all types, and cases involving open aorta and vena cava surgery were included in this study. Cases that involved contrast administration during the perioperative period, perioperative death, or with incomplete data were excluded from the analysis. Patient demographics and perioperative data were obtained from the chart review. Informed consents were obtained by the time of patient admission for later access of their medical records. Authors had access to information that could identify individual participants during or after data collection.

Covariates and definitions
The primary analysis was between patients underwent open surgeries of aorta or vena cava, with or without postoperative AKI, to evaluate the risk factors associated with postoperative AKI. AKI was defined as �26.5 μmol/L increase in serum creatine (SCr) level within the first 48 hours post-operation, or an increase in SCr levels from baseline by more than 50% during the first 7 postoperative days, according to the AKI criteria from the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Acute Kidney Injury, 2012 [11]. AKI was staged for severity according to the criteria presented in Table 1. Anemia: hemoglobin (Hb) (male) <120g / l, Hb (fmale) <110g / l. (Other definitions are included in Tables 2  and 3). Chronic kidney diseases (CKD): GFR<60ml/min/1.73m 2 . Hypoproteinemia: albumin <30g / l. Coronary heart disease: left ventricular ejection fraction (LVEF) <40%. Blood loss: Table 1. Staging of acute kidney injury.

Stage
Serum creatinine 1 1.5 to 1.9 times baseline or�0.3 mg/dl (�26.5 μmol/l) increase anesthesiologist estimated with blood recovered intraoperative blood salvage. Using of vasopressors: using the vasopressors drugs during operation. The baseline renal function was the last serum creatinine before surgery; the peak serum creatinine was the highest value of serum creatinine obtained during the first 7 days after surgery. The baseline levels of hemoglobin (Hb), hematocrit (HCT) and albumin (Alb) were obtained from the latest preoperative data, and the first test results after surgery were used as the postoperative results.

Data analyses
Data were expressed as a mean ± SD for continuous variables and as percentages for discrete variables. Continuous data were analyzed by Student's t test for equal variance or the Mann-Whitney test for unequal variance, and categorical valuables were investigated by the Pearson Table 2. Patients demographics and characteristics.

PLOS ONE
χ 2 or Fisher's exact test. A two-sided P value < .05 was considered significant. Logistic regression (adjusted for multiple covariates) was used to determine the odds ratio (OR) and the 95% confidence intervals (CI) associated with and without AKI. To adjust for additional unmeasured confounding variables, we fit a logistic regression model using the aforementioned covariates with the procedure type as the dependent variable. All covariates with P < .3 from univariate analysis were put into logistic regression model. Statistical analyses were performed using SPSS (Version 20.0. for Windows; SPSS, Inc.), and significance was assigned at P values < .05.  Tables 2 and 3. No significant differences were observed between the 2 groups in age, sex, preoperative blood pressure, BMI, Ace inhibitors/ ARBs use and preexisting comorbidities such as hypertension, hypoalbuminemia and CKD. The mean baseline serum creatinine in both the AKI and non-AKI groups was similar.

Perioperative characteristics of patients with AKI
Among all of the cases studied, the surgical duration of AKI groups was longer than the non-AKI groups (469.13±142.475min vs 400.89±100.39 min, p = .018). The median blood loss (ml) Table 3. Perioperative anemia of patients with and without acute kidney injury (AKI).

Risk factor of AKI
Open aorta and vena cava surgery, postoperative anemia, renal artery aneurysm repair, blood loss, and the use of intraoperative vasopressors, were all associated with AKI on univariate analysis (Tables 2 and 3

Discussion
Despite the development of endovascular procedures, open surgeries of aorta and vena cava are still used, especially in patients who are not suitable for endovascular procedures, and are associated with substantial mortality and complicated courses [1][2][3]. AKI in a common complication associated with open surgeries of aorta and vena cava. However, the incidence and risk factors of AKI in these conditions have not been adequately addressed. Ischemic-reperfusion injury is common following surgeries and causes AKI [12][13][14]. The incidence of AKI after surgery was different in different studies, and it was mainly related to  the observation from different patients [3,15]. In our study, we assessed the incidence and risk factors of AKI in patients underwent open surgery of aorta and vena cava. The prevalence of postoperative AKI was as high as 29.1%, indicating that AKI is a common complication in these patients. The patients included in this study underwent open surgery of aorta and vena cava, which may be extremely difficult due to the complicated anatomic structures and abundant collateral circulations [9,16]. These procedures are usually accompanied with prolonged length of surgery, higher bleeding risk, and more complicated perioperative course, placing the patients at increased risk of AKI [3,8,17]. In our study, the surgical duration of postoperative AKI groups was longer than that of no-AKI groups. The importance of AKI as a risk factor for mortality and we need to focus on high-risk patients for prevention and early identification of AKI and prompt treatment. However, we adopted the 2012 KIDIGO definition of AKI in our study, which is still based on increases in serum creatinine concentrations. New biomarkers of kidney injury, such as serum cystatin C (ScysC) Neutrophil Gelatinase-Associated Lipocalin (NGAL) and brain natriuretic peptide (BNP) may facilitate earlier detection of renal injury, and thus early intervention aimed at limiting the associated morbidity and mortality [18][19][20].
Postoperative AKI has been shown to be associated with early and long-term mortality and long-term risk of ESRD [4,5,21]. Thus adequate attentions are needed pertaining AKI following these surgeries.
It is noteworthy that AKI is more prevalent among those patients with more blood loss in our study. The mean blood loss during leiomyosarcoma and aortic aneurysm surgeries were 2400 ± 650 ml and 1500 ± 160 ml, and incidences of AKI after these procedures were up to 50% and 25.8%, respectively. Bleeding and postoperative anemia were associated with postoperative AKI, and multivariate analysis showed that postoperative anemia was an independent risk factor for AKI (OR, 5.202; 95% CI, 1.403-19.285). And vasopressors use during surgeries, which probably indicate more blood loss during the procedures, is associated with higher risk of postoperative AKI.
However, even without massive hemorrhage, the incidence of AKI after open renal artery aneurysm repair was higher comparing to other surgical procedures of the aorta and vena cava. Aortic cross clamping was a renal hazard for this group of patients, and AKI occurred in 21.5% of patients who underwent surgery with a suprarenal aortic cross clamp compared to 12.5% in those who didn't. Aortic cross clamping blocks effective renal perfusion and exposes the renal parenchyma to reduced oxygen tension, contributing to ischemia/reperfusion injury [14].
The kidney is especially vulnerable to hypoxic injury. Acute blood loss, hypovolemia, hemodilution or renal artery blocking during surgical processes may reduce regional oxygen supply, leading to physiological low oxygen tensions within the renal cortex and the medulla and microvascular dysfunction, and may result in acute kidney injury [12][13][14]. Furthermore, these conditions are associated with increased renal tubular oxygen consumption and oxidative stress, further confounding the imbalance of oxygen supply and demandz [13,14]. Postoperative anemia is the main predictor of postoperative AKI in our study, and other baseline characteristics that have been traditionally associated with AKI after other surgery types including age, baseline renal function, hypertension, and diabetes were not associated with postoperative AKI in our study. This may be attributed to the patient population selected, and limited case number in our study. Larger, multicenter, prospective studies may be needed to verify these conclusions.
Therefore, among patients undergoing open vascular surgery of aorta or vena cava, prevention and treatment may include avoiding unnecessary blood loss, ensuring optimal renal perfusion and ameliorating postoperative anemia. However, as shown in previous studies, treating perioperative anemia with blood transfusion didn't improve renal outcomes of patients undergoing surgery [22][23][24]. Furthermore, receiving intraoperative blood transfusion was associated with a higher risk of postoperative mortality, pulmonary complications, renal failure and infectious complications. Transfusions were associated with cytokine release, bacterial contamination, sepsis, metabolic disturbances, circulatory overload, hemolytic reactions, and risk of old blood [25]. Given these findings, other means to alleviate perioperative anemia are needed to consider. Erythropoietin (EPO) is a natural hormone produced in human body, and is a regulator of erythroid precursor cells. Evidences suggest that EPO has anti-apoptotic, anti-oxidative and anti-inflammatory properties, and is able to reduce the injury caused by ischemia/reperfusion of kidney in animal model [26,27]. Thus, EPO might be considered as a possible prophylactic intervention to prevent postoperative AKI.
This study has several limitations that need to be considered. First, the effects of unmeasured confounders on these relationships we describe cannot be dismissed because this is an observational study. Potentially important unmeasured confounders include the use of perioperative medications that may influence kidney function. Second, this is a single-center study with limited cases, and larger, multicenter, and prospective studies may be needed to further validate our finding.

Conclusions
In our study, AKI is a common complication in patients who undergo open aorta and vena cava surgeries, and postoperative anemia is the most relevant predictive factor of AKI. Strategies to minimize bleeding and anemia for all patients may be advisable. Further studies are needed to assess the impact of AKI on long term outcome and to examine preventive strategies to address potentially modifiable risk factors.