Patient Frailty Can Increase the Risk of Acute Kidney Injury after Cardiac Surgery: Pilot Study

Background: Acute kidney injury (AKI) is a severe common postoperative complication of cardiac surgery (CS). It increases the risk of mortality by up to 80%. Therefore, it is essential to have preoperative risk evaluation tools. Frailty is a marker of deterioration of physiologic systems and may be associated with AKI. Purpose: The study aimed to determine the utility of frailty as a predictor of AKI after CS. Method: We enrolled 91 patients undergoing CS with cardiopulmonary bypass to determine if they had frailty before surgery and were associated with postoperative AKI. The diagnosis of postoperative AKI was based on the serum creatinine criteria of the Acute Kidney Injury Network classification up to 7 days following CS. Results: The incidence of postoperative AKI was 62% in the frail group and 21% in the non-frail group. Frailty was associated with a higher risk of AKI (relative risk [RR] = 3.00, 95% CI 1.56 - 5.77, p = 0.00). In regression models, there were associa-tions between frailty and postoperative AKI. Conclusion: This study demonstrated that frailty could be a predictor for post-CS AKI. Therefore, frailty assessment should become an essential part of the preoperative evaluation to help the anesthesiologist to estimate the surgical risk and develop preoperative and transoperative strategies to preserve the renal function and improve the cardiac surgery outcome.


Introduction
Acute kidney injury (AKI) is a severe common postoperative complication of cardiac surgery (CS), with an incidence of 20% -70% [1] [2]. AKI is associated with extended hospital stay, intensive therapy unit stay, and increased mortality risk of up to 80% after CS; these complications significantly increase the surgery's cost, imposing a heavy load on the patients and public health systems [3].
Identifying at-risk patients is the first step in preventing postoperative AKI and its consequences [4]. But the available tools had not fulfilled the task. Despite different prediction models, the CS-AKI incidence remains high [5].
Several studies have outlined diverse risk factors to identify patients at risk for postoperative CS-AKI (post-CS AKI). Currently, there are multiple prediction models [5]. For example, the Cleveland Clinic Scoring System was developed in 2005. It is one of the most popular tools because it has the highest predictive value. It predicts severe AKI, but the prediction is weak for mild AKI; This leaves a significant proportion of patients at risk unidentified when it has been demonstrated that mild forms of AKI also have a substantial impact on morbidity and mortality [6].
The etiology of post-CS AKI is complex and unclear. Therefore, the diagnosis and prediction are complicated and interfere with adequate patient management [7]. Patients undergoing CS may experience multiple insults to the kidneys.
Renal blood flow, the primary determinant of renal oxygen delivery, is positively correlated to mean arterial pressure during cardiopulmonary bypass (CPB). This suggests that blood pressure is vital in renal autoregulation, and lower pressures are linked with an imbalance of oxygen supply and demand. The medullary portion of the kidney may be susceptible to ischemic damage caused by low resting PO2 [8]. Following CS, a systemic inflammatory response can be related to postoperative AKI [9]. The physiological changes inherent to aging make the elderly a high-risk population.
The elderly account for 50% of cardiac surgical procedures performed yearly and 78% of total morbidity and mortality [10]. In recent years, the identification of vulnerable elderly patients and frail patients has emerged as an essential indicator for outcomes after CS [10] [11].
Currently, the population is experiencing significant demographic changes; world reports have shown that most people can live beyond 60 years old. Related to this, elderly patients access health services continuously, and therefore the issue of frailty involves not only geriatricians but also surgeons and anesthesiologists [12].
Frailty syndrome has been proposed as a marker of biological age and deterioration of physiologic systems over time [13]. Conceptually, it is defined as the diminished capacity to recover from pathologic stressors due to aging-related impairments and decreased physiological reserves, resulting in increased mortality risk in various health conditions [14].
Kader KA et al. demonstrated an association between frailty and AKI in criti-S. Soto-Hopkins et al. World Journal of Cardiovascular Surgery cally ill patients [15]. Lee et al. in 2018 showed that AKI in survivors of critical illness predicted worse frailty status post-discharge, with important implications for clinical decision-making among AKI survivors and the need to understand the drivers of frailty to improve outcomes [16]. There is little information about the impact of frailty on AKI incidence and less data on patients who undergo CS with CPB.
We conducted this prospective cohort pilot study to assess the association of frailty and postoperative AKI in patients undergoing CS with CPB. reporting of this prospective observational study [17].

Cases Data
We included patients who underwent CS with CPB to determine if they had frailty syndrome before surgery and the association with postoperative AKI from August 1, 2018, to January 31, 2019. This sample exceeds the good practice recommendations for pilot studies of Lancaster et al. [18].
The inclusion criteria were patients ≥ 60 years old; undergoing CS with CPB; valve, coronary artery bypass graft surgery (CABG), and CABG with valve surgery combined. The exclusion criteria were: urgent and emergent surgeries; CPB time > 120 minutes; Aortic clamp > 90 minutes; sepsis; chronic kidney disease; cardiogenic shock; hypovolemic shock; Intra-aortic balloon pump counter pulsation (IABP); preoperative anemia and hematocrit (hct) levels < 21 mg/dl during CPB as a criterion of elimination.

Design
We applied the Fried frailty criteria to classify the study cohort. Patients were classified as frail if they met three or more of the following five criteria: [19] [20].

Statistical Analysis
Continuous variables were expressed as medians with interquartile ranges and as percentages for categorical variables. Data were statistically tested using Mann Whitney U or Chi-square tests when appropriate. A logistic regression analysis was used to evaluate the risk of AKI and its association with frailty status.
P-values < 0.05 were considered statistically significant. Studies and calculations were conducted using SPSS Statistics V 21.0 (IBM, NY, USA).

Results
Ninety-one patients met the inclusion criteria and were included in the pilot study. No patients met the elimination criteria. The baseline data of the cohort are shown in Table 2. Fifty-two of ninety-one (57%) patients were frail. Most frail patients met the Fried frailty criteria of weakness, exhaustion, and weight loss; however, in non-frail patients, the standard of weakness was the most frequent.
AKI occurred in 40 (44%) participants; 62% of frail patients developed AKI; however, in the group of non-frail patients, only 21% did. Stage 1 was the most common type of AKI (93%). One patient had AKI stage II and another stage III; both were frail. Notably, frailty was associated with a higher risk of AKI relative risk RR = 3.00, 95% CI 1.56 -5.77 p = 0.00 and non-frail patients relative risk RR = 0.48, 95% CI 0.33 -0.70 p = 0.00 (see Figure 1).
S. Soto-Hopkins et al.  There were no differences in CPB time, ACC time, and lactate during CPB.
Blood loss and blood product transfusion were similar (see Table 3). The only criterion without difference between AKI and non-AKI patients was slow gait speed, but the weight loss criterion was present in 76% of patients with postoperative AKI (Figure 2).

S. Soto-Hopkins et al. World Journal of Cardiovascular Surgery
The incidence of postoperative AKI in patients who had 3 -5 points in the CCS was 18.7% and 9.9% in those with the lower score RR = 1.84, 95% CI 1.20 -

Discussion
AKI is a common major complication that increases the morbidity and mortality risk after cardiac surgery. Identifying at-risk patients is the first step to implementing preventive actions that may improve patient outcomes. Several tools predict AKI, like the stratification and score systems and some biomarkers. Still, the incidence of CS-AKI remains high and imposes a heavy burden on patients and health care systems. This study demonstrated that frailty could be used as a marker for post-CS AKI.
The complete cohort of the study showed an AKI incidence of 44%, which is and surgery 7.1%. Malnutrition is common in elderly patients, and several studies have found that preexisting malnutrition is associated with poor outcomes in AKI patients [22].
Frailty is prevalent with increasing age and confers a high risk for adverse health outcomes, including mortality, institutionalization, falls, and hospitaliza- In CS, there are many risk factors for the development of AKI, including female sex, multiple comorbidities, previous cardiac surgery, COPD, DM, hypertension, obesity, hypercholesterolemia, and LVEF of <35%. Also, the intraoperative exposure to aminoglycoside antibiotics, the type of surgical procedure like complex cardiac surgery such as valve and coronary surgery combined and aortic arch surgery, and the CPB [24].
While CPB has been associated with an increased risk of AKI, just one sys-  [28]. Renal injury in AKI involves immune cells and cytokines [29].
Given that frailty is associated with worse postsurgical outcomes, including AKI, we need to modify and increase patient fitness before surgery. This concept is known as prehabilitation and is studied mainly in kidney and liver transplants [30]. Prehabilitation, in most studies, means increasing aerobic activity for several weeks before surgery with home and clinic programs. These programs include exercise, nutrition, and mental health interventions [31].

Strengths and Limitations
To our knowledge, this is the first study focused on assessing the association of frailty and postoperative AKI in patients undergoing CS. The results demonstrate that frailty is a novel predictor of AKI after CS, and frailty reduction strategies are essential as well as perioperative renal optimization. The study has limitations. This is a non-randomized study. In consequence, cause and S. Soto-Hopkins et al.

Conclusion
Acute kidney injury is a common postoperative complication of cardiac surgery with CPB, with an incidence of up to 44%. We found that frail patients have a three times higher risk of developing postoperative AKI after CS with CPB than non-frail patients (RR = 3.00, 95% CI 1.56 -5.77) and that the preoperative frailty status is comparable with the currently used risk stratifications models and very easy to assess. We demonstrated that frailty syndrome is a predictor for the development of AKI during the postoperative period of CS. The preoperative assessment of frailty may help design preoperative and transoperative strategies to reduce the risk of AKI in frail patients.

Compliance with Ethical Standards
This study was approved by the ethics committee and institutional review board of the Cardiology Hospital, National Medical Center Siglo XXI (CMN SXXI) of the Instituto Mexicano del Seguro Social (IMSS) in Mexico City. IBR number R-2018-3604-013.

Informed Consent
Written informed consents were obtained from all recruited patients.