Impact of Post-Procedural Acute Kidney Injury in Patients Undergoing Surgical Aortic Valve Replacement Versus Transcatheter Aortic Valve Implantation

) Impact of Post-Procedural Acute Kidney Injury in Patients Undergoing Surgical Aortic Valve Replacement Versus Transcatheter Aortic


Introduction
Acute Kidney Injury (AKI) is one of the most significant complications in patients undergoing Surgical Aortic Valve Replacement (SAVR) or Transcatheter Aortic Valve Implantation (TAVI) for severe aortic valve stenosis [1]. Its incidence varies between 4% and 49% depending on AKI definition and study population characteristics [2,3]. AKI has been shown to be associated with increased short-and long-term morbidity and mortality after cardiothoracic surgery [4,5]. The pathophysiological mechanisms underlying the onset of AKI in SAVR versus TAVI patients are different. In patients undergoing SAVR, such a complication may be related to the duration of the procedure and the use of Cardiopulmonary Bypass (CPB) [2,6], on the other hand, in TAVI patients, it may be triggered by the administration of intravenous contrast, the presence of a short period of severe hypotension (e.g during rapid pacing and valve deployment), and the increased risk of embolization due to aortic catheterization [1]. To date, only few studies compared incidence and evolution of AKI in SAVR versus TAVI patients [7,8]. The aim of the present analysis is to understand if the onset of AKI has a different impact on short-and mid-term outcomes in these two groups of patients.

Patients and Methods
The study was conducted in accordance with the declaration of Helsinki and the study design was approved by the local Ethics Committee at the Mauriziano Hospital, Turin -Italy (protocol number 260-2022). Informed consent was obtained from all patients.

Patient Population And Study Design
Consecutive patients undergoing SAVR or TAVI for severe aortic valve stenosis from September 2017 to December 2019 at the Mauriziano Hospital were included in the analysis. The diagnosis of severe aortic valve stenosis was based on the best practice of the European Society of Cardiology/European Association for Cardiothoracic Surgery guidelines [9]. Exclusion criteria were reoperations or valve-in-valve procedure and the need for concomitant procedures (i.e. coronary artery bypass grafting, mitral valve replacement, percutaneous coronary intervention). Each patient was allocated to the most appropriate approach after an accurate Heart Team evaluation involving cardiothoracic surgeons, cardiologists, anesthesiologists, and radiologists assessing clinical history, blood tests, electrocardiogram, transthoracic echocardiography, computed tomography, and cardiac catheterization of the patients. The Euroscore II was also calculated for each patient and used as a further reference of evaluation [10]. Baseline characteristics such as age, sex, Body Mass Index (BMI), hypertension, dyslipidemia, diabetes mellitus, smoking, peripheral vascular disease, New York Heart Association (NYHA) class, and serum creatinine (SCr) level were recorded in both groups. The pre-procedural estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula [11]. Based on the eGFR, patients were divided into five groups following the Kidney Disease Outcomes Quality Initiative (KDOQI) classification for Chronic Kidney Disease (CKD) [12]: All TAVI patients with pre-procedural CKD stage III-V (eGFR ≤ 60 ml/min) received a prophylactic treatment with 0,9% saline solution, N-acetylcysteine, and sodium bicarbonate. The urgency for the intervention was also investigated in all patients. In the SAVR group, CPB and aortic cross-clamp times were listed, as well as the amount of intravenous contrast used during TAVI.

Surgical Techniques
The operative techniques have been previously described [13,14]. Briefly, SAVR were performed using sternotomy or midsternotomy, central aortic cannulation, hypothermic CPB, aortic cross-clamping, and myocardial protection with antegrade blood or crystalloid cardioplegia. TAVI were performed mainly by a transfemoral approach while alternative accesses, such as transcarotid, trans-subclavian, transapical, and transcaval, were used only in few patients when the former approach was not feasible. Both self-expandable and balloon-expandable prosthesis were implanted. If necessary, a valvuloplasty was performed before or after prosthesis implantation.
The secondary endpoints were need and duration of RRT, Intensive Care Unit (ICU) and in-hospital length of stay, KDIGO stage at discharge, eGFR at 1 year of follow-up, and 30-day and 1-year mortality.
All the patients received a follow-up visit at 3 months after surgery, a blood test at 1 year, and a follow-up phone call at 1 year. The follow up was completed on December 13, 2020.

Statistical Analysis
Data were collected into a dedicated database and retrospectively analyzed. For continuous variables data were expressed with mean and Standard Deviation (SD); for categorical variables data were represented with frequency and percentage. Differences between groups were assessed using the Student's test for continuous variables and chi-square test or Fisher's exact test for categorical variables. One-year mortality was assessed and reported using the Kaplan-Meier method. The long-rank test was used to compare the survival distribution among different AKI stages in the two groups. All p-values were two-sided and a p-value <0.05 was considered statistically significant. All analyses were performed with SPSS 26.0 (IBM, Chicago, USA).

Results
From September 2017 to December 2019, 457 consecutive patients with diagnosis of severe aortic valve stenosis underwent SAVR (n=201, 44.0%) or TAVI (n=256, 56.0%) at the Mauriziano Hospital in Italy and were enrolled in the present analysis. Baseline characteristics of the two groups are described in Table 1. Patients in the TAVI group were older (82.7 ± 4.9 vs 71.6 ± 9.8, p<0.001), with higher incidence of NYHA class III-IV (54.3% vs 38.8%, p=0.001), and higher Euroscore II (5.7 ± 5.9 vs 2.4 ± 3.1, p<0.001), when compared to the SAVR group. Patients in the SAVR group had higher incidence of smoking ( aNYHA class was not available for 14 patients in the SAVR group and 1 patient in the TAVI group.  .73) were similar in AKI vs no-AKI patients. In the TAVI group, the amount of intravenous contrast used during the procedure was higher in AKI patients (99.7 ± 54.0 vs 71.9 ± 29.7, p=0.001) ( Table 3). In both groups, AKI patients had longer ICU length of stay (5.0 ± 6.6 vs 2.0 ± 6.6, p=0.004 for SAVR; 7.0 ± 8.0 vs 2.0 ± 7.0, p=0.01 for TAVI) and in-hospital length of stay (13.0 ± 10.3 vs 9.8 ± 10.3, p=0.05 for SAVR; 16.7 ± 12.9 vs 8.4 ± 12.3, p=0.01 for TAVI) when compared to no-AKI patients (   At discharge, the percentage of patients still in AKI was significantly higher in the TAVI group when compared to the SAVR group (n=8/15 [53.3%] vs 9/58 [15.5%], p<0.001). Particularly, in the SAVR group, 2 patients with diagnosis of AKI II were discharged in AKI I, 2 patients with diagnosis of AKI II and 1 patient with diagnosis of AKI III were discharged in AKI II, and 4 patients with diagnosis of AKI III were discharged in the same category. In the TAVI group, 3 patients with diagnosis of AKI I, 1 patient with diagnosis of AKI II, and 1 patient with diagnosis of AKI III were discharged in AKI I while 3 patients in AKI III were discharged in the same category.

Discussion
In this single-center retrospective analysis evaluating short-and mid-term outcomes associated with post-procedural AKI in patients undergoing SAVR vs TAVI for severe aortic valve stenosis, we found that despite a higher incidence of AKI in SAVR patients, it lasted longer in TAVI patients. Post-procedural AKI was associated with higher 30-day and 1-year mortality in both groups. TAVI patients with severe AKI had a lower estimate 1-year survival compared to SAVR patients in the same category. In developed countries, calcific aortic valve stenosis represents the most common valvulopathy with a prevalence of 3% among people over the age of 75 [16]. A strong association between aortic valve stenosis and renal dysfunction is reported: leaflet calcification is accelerated in patients with chronic renal dysfunction due to an altered phosphor and calcium metabolism, and a long-standing aortic valve stenosis leads to decreased kidney perfusion due to reduced cardiac output [17]. SAVR remains the gold standard for the treatment of aortic valve stenosis but in recent years the transcatheter approach has emerged as an attractive alternative [18][19][20][21]. Recent guidelines from the European Society of Cardiology/European Association for Cardiothoracic Surgery and the American College of Cardiology/American Heart Association have highlighted that the choice between the two abovementioned approaches needs to be based on an accurate Heart Team evaluation of patient's characteristics, comorbidities, and risk of developing post-procedural complications [9,22]. Among these, post-procedural AKI is a frequent complication of both surgical and transcatheter procedures. In our analysis, the incidence of AKI was 28.9% among SAVR patients and 5.9% among TAVI patients in accordance with literature findings, even if post-procedural AKI in TAVI patients tends to be slightly higher [2][3][4].
Furthermore, different studies have reported a worse prognosis in patients who developed AKI after cardiothoracic surgery. In patients undergoing SAVR, the onset of AKI is associated with higher in-hospital mortality with an incidence of 15.0% in patients with severe renal dysfunction versus 2.9% in patients without kidney injury [3]. In TAVI patients, AKI is related with an increased 30-day mortality which ranges from 10% to 30% and a 3-fold increase in 1-year mortality [7]. In the present analysis, a significantly higher 30-day mortality was recorded among AKI patients in both SAVR (8.6% vs 0.7%) and TAVI group (20.0% vs 0.4%) and this finding persisted for 1-year mortality (13.8% vs 3.5% for SAVR and 33.3% vs 8.7% for TAVI). We also found that patients who developed AKI in both groups presented worse baseline characteristics compared to patients who did not such as lower eGFR and higher incidence of CKD II-V, as previously described [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. The higher mortality rates in TAVI patients is not surprising, they are usually older, frailer, and with more comorbidities than surgical patients, as a consequence, AKI has a higher impact on their outcomes. In our analysis, TAVI patients were older, with higher Euroscore II, lower eGFR, and higher rate of CKD II-V. Despite the incidence of AKI was higher in SAVR patients, kidney injury lasted longer in the TAVI group. At discharge, 84.5% of SAVR patients had a complete kidney function recovery versus 46.7% in the TAVI group. Several studies have focused on AKI duration as an important risk factor for worse clinical outcomes. Patients developing a long-standing AKI have a worse prognosis when compared to patients with transient AKI or no AKI, including progressive kidney disease and increased in-hospital and long-term mortality. Thongprayoon and collogues reported that, at discharge, the 13% of TAVI patients who remained in AKI had a significantly higher 1-year mortality [24]. This finding is comparable to our results, TAVI patients had a higher incidence of persisting AKI at discharge and an increased 1-year mortality. Furthermore, TAVI patients with severe AKI had a lower estimate 1-year survival compared to SAVR patients in the same category.
A higher incidence of post-procedural AKI in the SAVR group has been reported in literature which is unremarkable considering different pathophysiological mechanisms underlying this post-procedural complication. In the surgical group, AKI is related to hypoperfusion, ischemia-reperfusion injury, inflammation, and oxidative stress during CPB [2], while in the TAVI group, kidney injury is mainly due to intravenous contrast administration. Previous studies have showed that prolonged CPB time increases the incidence of post-procedural AKI [25,26]. Fisher and collogues evaluated the effect of CBP time on kidney function and found that CBP duration was significantly longer in patients with post-procedural AKI (166 ± 77 min versus 107 ± 40 min, p<0,001). In our analysis, however, we did not find a significant association between CPB time and post-procedural AKI. The association between amount of intravenous contrast and onset of AKI after TAVI is controversial. Podolecka and colleagues evaluated pre-procedural and post-procedural eGFR and SCr level in 39 TAVI patients with a mean intravenous contrast volume of 187 ± 91 ml. They found that the intravenous contrast amount was not correlated with a decreased renal function [27]. Similar findings were reported by Nguyen and colleagues who showed that intravenous contrast load was not associated with a higher incidence of renal failure [28]. On the other hand, Yamamoto and colleagues reported a higher incidence of AKI in patients in which a higher volume of intravenous contrast was used [29]. In the present analysis, we showed that the onset of post-procedural AKI is significantly related to the amount of intravenous contrast used during the procedure. A larger patient population and a longer follow up are mandatory to confirm these findings.
This study must be interpreted in the setting of its limitations. First, this is a retrospective analysis and thus susceptible to the usual biases associated with these series [30]. Second, the results herein presented are specific to a single-center and may not be easily applied across all hospital and geographic settings. Finally, comparisons among groups may be underpowered to detect significant differences in clinical outcomes due to the limited number of patients.

Conclusion
To conclude, post-procedural AKI is a risk factor for 30-day and 1-year mortality in both SAVR and TAVI patients. Despite the higher AKI incidence in SAVR patients, AKI lasted longer in TAVI patients. TAVI patients who develop a severe AKI, according to KIDGO criteria, had a lower estimate 1-year survival compared to SAVR patients in the same category. An accurate Heart Team evaluation including a nephrological examination for the patients with higher risk of post-procedural AKI is mandatory in order