Preoperative vascular dysfunction is associated with acute kidney injury after cardiac surgery

Introduction

Cardiac surgery-associated acute kidney injury (CSA-AKI) which is reported to occur in 5–30% of the patients undergoing cardiac surgery is associated with higher risk of in-hospital mortality and poor long-term outcomes (1). Several risk factors for CSA-AKI have been reported including female gender, preoperative creatinine, ejection fraction, cardiopulmonary bypass time, and insufficient perioperative blood pressure management (2).

Preoperative aortic stiffness measured by pulse wave velocity (PWV) has also been reported to be associated with CSA-AKI in patients undergoing coronary artery bypass grafting (CABG) (3). Barotrauma inflicted on glomeruli in a stiff vascular system has been suggested to be the mechanism of kidney injury (4). Along with vascular stiffness, endothelial function mediated by nitric oxide, also plays a major role in the maintenance of vascular function. Endothelial dysfunction is a major risk factor for cardiovascular event (5). Endothelial dysfunction promotes inflammation of the vasculature including up-regulation of adhesion molecules and leukocyte adherence resulting in atherosclerotic changes. Endothelial dysfunction is also a prominent feature of end-stage renal disease (5,6). However, the association between preoperative endothelial function and incidence of postoperative CSA-AKI in patients undergoing valve surgery is unknown.

Several serum biomarkers have been reported for their involvement in vascular function. Cell adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1) is associated with arterial stiffness. Expression of VCAM-1 promotes arterial stiffening and it is correlated with PWV and cardiovascular event (7-9). Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor, which regulates nitric oxide-reactive oxygen species balance (10,11). ADMA has been used to evaluate endothelial function and has also been reported to be a possible therapeutic target to prevent cardiovascular events (12). Despite their known association with vascular function and cardiovascular events, their association with postoperative outcomes in patients undergoing cardiac surgery is not reported.

The purpose of this study was to evaluate the association between preoperative vascular function and incidence of CSA-AKI in patients undergoing valve surgery using cardiopulmonary bypass. The hypothesis of this study was that endothelial dysfunction and increased vascular stiffness is associated with increased incidence of CSA-AKI. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1291/rc).

Methods

From April 2019 to April 2020, 40 consecutive patients undergoing valve surgery using cardiopulmonary bypass were enrolled in this prospective observational study. Flow-mediated dilation (FMD) and PWV were measured before surgery for the evaluation of endothelial function and vascular stiffness, respectively. Blood test was also performed for the measurement of serum biomarkers including ADMA and VCAM-1. The association between vascular function and CSA-AKI, which was diagnosed following the Kidney Disease Improving Global Outcomes (KDIGO) criteria without diuresis, was evaluated. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Institutional Ethics Board of Saitama Medical Center, Jichi Medical University (No. S18-098) and informed consent was taken from all the patients.

Vascular function measurements

PWV measurement

The PWV measurements were performed using a non-invasive device (Omron Colin, Tokyo, Japan). Recording of the two different pulse waves were measured simultaneously at two transducers placed on the arm and the ankle. The pulse transit time and the distance between the two transducers were used to calculate PWV [PWV (cm/s) ¼ travel distance (cm)/transit time (s)] (13).

FMD measurement

Endothelial function was evaluated by FMD (FMD: UNEXEF38G, UNEX Corporation, Nagoya, Japan). High-frequency ultrasonographic imaging was used to evaluate the inner diameter of the brachial artery before and after the release of pressurized cuff applied to the forearm for 5 minutes. Arterial dilation was calculated as percent dilation of the brachial artery after the release of the cuff [FMD (%) = (max diameter − resting diameter)/resting diameter ×100%] (13). All medication was stopped prior to measurement.

ADMA and VCAM-1 measurement

The serum samples were collected and were kept at −80 ℃. ADMA enzyme-linked immunosorbent assay (ELISA) Kit (Immundiagnostik AG, Bensheim, Germany) and VCAM-1 ELISA kit (R&D Systems Inc., Minneapolis, MN, USA) were used to detect ADMA and VCAM-1 as directed by the manufacturer’s instruction.

Evaluation of acute kidney injury

Creatinine level measured at the time of hospital admission, 2 days prior to surgery, was used for the baseline serum creatinine (sCr) level. Creatinine level measured at 48 hours after the surgery was used for the diagnosis of CSA-AKI based on the KDIGO criteria without diuresis. Patients meeting any of the KDIGO criteria were considered to have CSA-AKI (14).

Statistical analysis

Normal distribution of the data was assessed using the Kolmogorov-Smirnov test. For comparing two continuous data that were normally distributed, the Student’s t-test (mean ± standard deviation) was used. For comparing continuous data that were not normally distributed, Mann- Whitney U test [median (interquartile range)] was used. Pearson’s correlation ratio was used for evaluating the association between two normally distributed continuous variables. For comparing categorical variables, Fisher’s exact test was used (n, %). Multivariable analysis for CSA-AKI and preoperative vascular function was performed including preoperative creatinine level and cardiopulmonary bypass time, which have been reported to be associated with CSA-AKI in the previous reports (2,15). P values less than 0.05 (P<0.05) were considered significant, and all analyses were performed using Stata (version 13.1, Stata Corp, College Station, TX, USA) and Prism 8 (GraphPad Software Inc., La Jolla, CA, USA).

Results

The demographics of the patients included in the study are shown in Table 1. The mean age of the patients was 72±8.2 years old and 60% were male. All patients underwent valve surgery with 2 patients undergoing concomitant CABG. Preoperative FMD and PWV were 6.3%±2.58% and 1,554±386.6 cm/s, respectively.

There was a significant correlation between ADMA and VCAM-1 [r=0.50, 95% confidence interval (CI): 0.224 to 0.703, P=0.001] (Figure 1A). There also was a significant correlation between FMD and ADMA (r=−0.42, 95% CI: −0.647 to −0.125, P=0.007), and FMD and VCAM-1 (r=−0.42, 95% CI: −0.646 to −0.122, P=0.007) (Figure 1B,1C). Although not statistically significant, there was a weak correlation between PWV and ADMA (r=0.25, 95% CI: −0.068 to −0.520, P=0.12) and PWV and VCAM-1 (r=0.21, 95% CI: −0.114 to 0.486, P=0.20) (Figure 1D,1E).

Figure 1 Scatter plot of vascular function measurements. There was a significant correlation between ADMA and VCAM-1 (A). FMD was correlated with ADMA (B) and VCAM-1 (C). There was no significant correlation between PWV and ADMA (D), and PWV and VCAM-1 (E). VCAM-1, vascular cell adhesion molecule-1; ADMA, asymmetric dimethylarginine; FMD, flow-mediated dilation; PWV, pulse wave velocity.

There were 11 patients (27.5%) who developed CSA-AKI after surgery. No patients required hemodialysis, and there were no in-hospital deaths. Patients with CSA-AKI were more likely to have hypertension (no AKI: 58.6% vs. AKI: 90.9%, P=0.07) and higher preoperative creatinine level (no AKI: 0.85±0.369 mg/dL vs. AKI: 1.25±0.478 mg/dL, P=0.007). Intraoperative blood loss [median (interquartile range): no AKI: 315 (234.0 to 465.0) mL vs. AKI: 340 (195.0 to 578.0) mL, P=0.76], blood transfusion (no AKI: 24.1% vs. AKI: 54.5%, P=0.13) and perioperative fluid balance [median (interquartile range): no AKI: 8,685 (7,670.0 to 11,801.0) mL vs. AKI: 9,043 (7,892.5 to 11,512.0) mL, P=0.32] were similar between patients with and without CSA-AKI. Although the types of surgery performed were similar between patients with and without CSA-AKI, patient with CSA-AKI had longer cardiopulmonary bypass time (no AKI: 110±33.4 min; AKI: 134±43.9 min, P=0.07) (Table 1).

For vascular function, FMD was lower in patients with CSA-AKI (no AKI: 6.9%±2.57% vs. AKI: 4.6%±1.77%, P=0.009) and PWV was higher in patients with CSA-AKI (no AKI: 1,467±296.4 cm/s vs. AKI: 1,784±506.7 cm/s, P=0.02) (Figure 2A,2B). ADMA was similar in patients with and without CSA-AKI (no AKI: 0.60±0.091 µmol/L vs. AKI: 0.65±0.099 µmol/L, P=0.14) (Figure 2C). However, VCAM-1 was higher in patients with CSA-AKI (no AKI 696±247.5 ng/mL vs. AKI: 879±196.2 ng/mL, P=0.03) (Figure 2D).

Figure 2 Comparison of vascular function measurements between patients with and without AKI. FMD was significantly lower in patients with AKI (A) and PWV was significantly higher in patients with AKI (B). ADMA was similar in patients with and without AKI (C). VCAM-1 was higher in patients with AKI (D). FMD, flow-mediated dilation; AKI, acute kidney injury; PWV, pulse wave velocity; ADMA, asymmetric dimethylarginine; VCAM-1, vascular cell adhesion molecule-1.

Multivariable analysis showed that preoperative FMD was an independent risk factor for CSA-AKI [odds ratio (OR): 0.54, 95% CI: 0.294 to 0.998, P=0.049) (Table 2).

Discussion

Vascular function plays a major role in protection of major organs. By Windkessel effect, the aorta manages constant flow to the peripheral by its cushioning effect (16). Loss of cushioning effect by aortic stiffening results in increase in PWV, thus increasing volume overload to the peripheral. Increase in PWV also results in earlier reflection of the return wave to the aortic root, which results in decreased diastolic pressure, thus causing lower coronary perfusion and increased pulse pressure (16).

Increase in PWV has been shown to result in kidney disease progression, and major cardiovascular event including heart failure and stroke (16). Further, preoperative PWV measurement in patients undergoing elective CABG has been shown to independently predict CSA-AKI. CSA-AKI is associated with poor prognosis in which even a small increase (0.3–0.5 mg/dL) in sCr is associated with a nearly 3-fold increase in 30-day mortality, while a larger increase of >0.5 mg/dL is associated with more than 18-fold increase in 30-day mortality (17). Further, CSA-AKI is associated with longer hospitalization and higher medical costs (1).

Previous reports have shown that female gender, preoperative cardiac function, diabetes mellitus, peripheral vascular disease, chronic obstructive pulmonary disease, emergent surgery, reintervention, intraoperative use of aprotinin, cardiopulmonary bypass time, perioperative blood pressure management and preoperative renal impairment were independent risk factors for the development of CSA-AKI (2,15,18). Only few studies have shown the association between vascular function and CSA-AKI. A study by Greenwood et al. showed that PWV and estimated glomerular filtration rate were associated with CSA-AKI in patients undergoing CABG (3). Choi et al. also showed that PWV was a predictor of CSA-AKI in patients undergoing off-pump CABG (19). For valvular disease, earlier work by Kidher et al. reported a correlation between preoperative PWV and CSA-AKI in patients with normal to mild renal impairment undergoing aortic valve replacement (20). The present study also showed that in patients undergoing elective valve surgery requiring cardiopulmonary bypass, higher preoperative PWV was associated with higher incidence of CSA-AKI.

Along with vascular stiffness, endothelial function is another important factor in preservation of vascular function. Vascular endothelium is an active paracrine, endocrine, and autocrine organ that play a major role in the regulation of vascular tone and the maintenance of vascular homeostasis (5). Endothelial dysfunction results in progression of vascular inflammation including up-regulation of adhesion molecules, increased chemokine secretion, leukocyte adherence, and vascular smooth muscle cell proliferation, thus causing atherosclerosis. This mechanism is caused by the imbalance of production and availability of endothelium-derived relaxing and contracting factors including nitric oxide (5). Endothelial function can be measured non-invasively by FMD, which measures nitric oxide induced vasorelaxation. The result of the present study showed that preoperative FMD was independently associated with CSA-AKI after normalizing for cardiopulmonary bypass time and preoperative creatinine level. Previous studies have shown that use of cardiopulmonary bypass was associated with endothelial dysfunction after surgery, which may last up to 1 week (4,21). These results may suggest that abundancy in circulating nitric oxide may protect from vascular inflammation by its anti-inflammatory effect in patients undergoing cardiopulmonary bypass, thus minimizing the effect of cardiopulmonary bypass induced inflammation (22). Further, preservation of endothelial function may protect from local shear stress of the arterial wall by its cushioning effect, thus preventing major organ damage from hemodynamic volume overload.

Several biomarkers have been reported for the assessment of vascular function. Among several metabolic pathways, L-arginine (Arg) can be oxidized by endothelial NOS for the production of nitric oxide which is essential for the maintenance of vascular function. On the other hand, protein arginine residues can be methylated in various ways resulting in formation of ADMA by subsequent proteolysis. Although ADMA is predominantly absorbed by the endothelial cells, it competes with arginine for binding to NOS and is associated with atherosclerotic change and cardiovascular event (22). During the progression of vascular inflammation, VCAM-1 promotes adhesion and transmigration of inflammatory cells to the interstitium. VCAM-1 is upregulated in atherosclerosis, stroke, heart failure with preserved ejection fraction, atrial fibrillation, hypertension, and ischemia, which is also used as a biomarker for cardiovascular diseases (9). The present study has shown a significant correlation between ADMA and VCAM-1. FMD was also associated with ADMA and VCAM-1 showing significant interaction of these proteins in the homeostasis of vascular function. Multivariable analysis however, showed that FMD was an independent risk factor for CSA-AKI. This result suggested the importance of physiological assessment of vascular function, which represent the outcomes of the interactions among these inflammatory proteins.

Limitation

The major limitation of this study was the small sample size. However, the mean FMD of the whole population in the present study was 6.3% with standard deviation of 2.57%. The difference in FMD of patients with (n=11) and without AKI (n=19) was 2.3%, which provides statistical power of 0.72 with alpha error of 0.05. Further study with more sample size is preferable to confirm this result. Second, this study only shows association of vascular function with incidence of CSA-AKI. Further study is needed to assess whether intervention to improve vascular function such as cholesterol lowering drug, antihypertensive therapy, smoking cessation, angiotensin converting enzyme inhibitor therapy, vitamin E, statin and L-arginine therapy can prevent from CSA-AKI (5,23,24).

Conclusions

Vascular dysfunction including increased vascular stiffness and endothelial dysfunction may have significant effect on development of CSA-AKI. Preoperative assessment of vascular function including serum VCAM-1, FMD, and PWV may be useful in evaluation of potential risk of CSA-AKI in patients undergoing cardiac surgery.

Acknowledgments

Funding: This study was funded by JSPS KAKENHI [Nos. JP18K16400 (to D.H.) and JP21K16500 (to D.H.)] from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1291/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1291/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1291/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1291/coif). D.H. reports that this study was funded by JSPS KAKENHI (Nos. JP18K16400 and JP21K16500) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Institutional Ethics Board of Saitama Medical Center, Jichi Medical University (No. S18-098) and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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