Role of Major Cardiovascular Surgery-Induced Metabolic Reprogramming in Acute Kidney Injury in Critical Care

Life Sciences Cardiovascular System Nephrology Medicine Biochemistry
major cardiovascular surgery metabolism metabolomics amino acid TCA cycle citric acid acylcarnitines acute kidney injury

The Role of Major Cardiovascular Surgery-Induced Metabolic Reprogramming in Acute Kidney Injury: A Metabolomics Study

Academic Background

Cardiovascular diseases are the leading cause of death worldwide, accounting for over 17.9 million deaths annually, which is 32% of all deaths. As the disease burden increases, about one-third of patients may require surgical intervention at some point in their lives. Currently, more than 2 million cardiac surgeries are performed globally each year. Although cardiac surgery plays a crucial role in cardiovascular health, it also carries significant risks of morbidity and mortality. Postoperative recovery often involves an inflammatory host response, with myocardial ischemia, endothelial dysfunction, and ischemia-reperfusion injury contributing to varying degrees of organ dysfunction. However, our understanding of the molecular mechanisms of postoperative stress responses remains limited, hindering evidence-based improvements in patient outcomes.

In recent years, advances in metabolomics technology have provided new tools for studying metabolic changes after cardiovascular surgery. Metabolomics can comprehensively characterize postoperative metabolic patterns, revealing metabolic features associated with surgical stress and postoperative organ dysfunction. This study aims to explore the metabolic reprogramming induced by major cardiovascular surgery and its potential role in postoperative acute kidney injury (AKI) through metabolomics approaches.

Paper Source

This paper was authored by Tiago R. Velho et al., with authors from multiple research institutions, including the Cardiothoracic Surgery Research Unit and the Center for Disease Mechanisms Research at the Faculty of Medicine, University of Lisbon, Portugal. The paper was published in Intensive Care Medicine in 2024, with the DOI 10.1007/s00134-024-07770-4.

Research Workflow

1. Study Subjects and Grouping

This was a prospective observational study that included 53 patients undergoing major cardiovascular surgery. Patients were divided into three groups based on the type of surgery: - CPB Group: Cardiac surgery with cardiopulmonary bypass (CPB), n = 33. - No CPB Group: Cardiac surgery without CPB, n = 10. - Vascular Surgery Group: Major vascular surgery, n = 10.

2. Sample Collection and Processing

Peripheral blood samples were collected preoperatively, and at 6 hours and 24 hours postoperatively for each patient. Serum samples were separated by centrifugation and stored at -80°C for subsequent metabolomics analysis.

3. Metabolomics Analysis

Untargeted metabolomics was performed using mass spectrometry to quantify 8,668 metabolic features in serum samples. Specific steps were as follows: - Sample Pretreatment: 100 μL of serum was mixed with 400 μL of methanol/ethanol mixture (4:1, v/v), vortexed for 5 minutes, and centrifuged to remove proteins. - Metabolite Separation: Hydrophilic interaction chromatography (HILIC) and reversed-phase chromatography (RP) were used for metabolite separation. - Mass Spectrometry Detection: High-resolution tandem mass spectrometry (Q-Exactive Focus) was employed for metabolite detection, and data were processed using Compound Discoverer 3.0 software.

4. Data Analysis

Linear mixed-effect models were used to analyze metabolite changes at different time points, adjusted for age, sex, and body mass index. Significant metabolites were screened using multiple testing corrections (Bonferroni and Benjamini-Hochberg methods). Additionally, metabolic pathway analysis and principal component analysis (PCA) were conducted to compare the metabolic profiles across different surgical groups.

Key Results

1. Metabolic Features in the CPB Group

In the CPB group, 772 metabolites showed significant changes across the three time points (p < 2.8e-05). These metabolites were primarily enriched in protein metabolism-related pathways, with glycine and serine metabolism being the most prominent. Moreover, the metabolic profile of the CPB group was distinctly different from the other two groups, exhibiting a unique pattern of metabolic reprogramming.

2. Metabolic Features in AKI Patients

In the CPB group, 42.4% of patients (14 cases) developed AKI postoperatively, with 33.3% classified as stage 1 AKI and 9.1% as stage 2 AKI. The metabolic profiles of these patients showed a significant increase in protein catabolism, including the degradation of valine, leucine, and isoleucine, along with disruptions in the tricarboxylic acid cycle (TCA cycle) and accumulation of acylcarnitines.

3. Association Between Metabolites and AKI

Logistic regression analysis revealed that preoperative levels of O-3-methylglutarylcarnitine were significantly associated with postoperative AKI (p = 0.035), with an area under the curve (AUC) of 90.7% for predicting postoperative AKI. Additionally, preoperative citric acid levels were significantly elevated in AKI patients.

Conclusion

This study is the first to reveal the significant metabolic reprogramming induced by major cardiovascular surgery, particularly those involving CPB. Postoperative AKI patients exhibited specific metabolic features, including increased protein catabolism, disruption of the TCA cycle, and accumulation of acylcarnitines. These findings provide important metabolic insights for designing interventions to reduce postoperative organ dysfunction, including AKI.

Study Highlights

  1. Unique Metabolic Signature: The metabolic reprogramming induced by CPB surgery is dominated by protein metabolism, significantly differing from other types of surgery.
  2. Metabolic Predictive Biomarker for AKI: Preoperative levels of O-3-methylglutarylcarnitine can serve as a predictive biomarker for postoperative AKI.
  3. Disruption of Metabolic Pathways: The metabolic profiles of AKI patients show significant disruptions in the TCA cycle and acylcarnitine metabolism, suggesting their potential roles in postoperative renal injury.

Research Value

Through metabolomics approaches, this study reveals the metabolic changes following major cardiovascular surgery and their association with postoperative AKI. These findings not only provide new perspectives for understanding the molecular mechanisms of postoperative organ dysfunction but also offer potential targets for developing metabolism-based therapeutic strategies. For example, modulating acylcarnitine synthesis or preoperative nutritional interventions may help improve outcomes for cardiac surgery patients.