Metabolomics window into the role of acute kidney injury after coronary artery bypass grafting in diabetic nephropathy progression

Abstract

Introduction Metabolomics has emerged as a valuable tool to discover novel biomarkers and study the pathophysiology of diabetic nephropathy (DN). However, the effect of postoperative acute kidney injury (AKI) on diabetes mellitus (DM) to chronic DN progression has not been evaluated from the perspective of metabolomics. Methods A group of type 2 diabetes mellitus (T2DM) inpatients, who underwent off-pump coronary artery bypass grafting (CABG), were enrolled in our study. According to whether postoperative AKI occurred, patients were grouped in either the AKI group (AKI, n = 44) or the non-AKI group (NAKI, n = 44). Urine samples were collected from these patients before and 24 h after operation. Six patients from the AKI group and six patients from the NAKI group were chosen as the pilot cohort for untargeted metabolomics analysis, with the goal of identifying postoperative AKI-related metabolites. To understand the possible role of these metabolites in the chronic development of renal injury among T2DM patients, trans-4-hydroxy-L-proline and azelaic acid were quantified by targeted metabolomics analysis among 38 NAKI patients, 38 AKI patients, 46 early DN patients (DN-micro group), and 34 overt DN patients (DN-macro group). Results Untargeted metabolomics screened 61 statistically distinguishable metabolites in postoperative urine samples, compared with preoperative urine samples. Via Venn diagram analysis, nine of 61 were postoperative AKI-related metabolites, including trans-4-hydroxy-L-proline, uridine triphosphate, p-aminobenzoate, caffeic acid, adrenochrome, δ-valerolactam, L-norleucine, 5′-deoxy-5′-(methylthio) adenosine, and azelaic acid. By targeted metabolomics analysis, the level of trans-4-hydroxy-L-proline increased gradually from the NAKI group to the AKI, DN-micro, and DN-macro groups. For azelaic acid, the highest level was found in the NAKI and DN-micro groups, followed by the DN-macro group. The AKI group exhibited the lowest level of azelaic acid. Conclusions The detection of urinary trans-4-hydroxy-L-proline after AKI could be treated as an early warning of chronic DN progression and might be linked to renal fibrosis. Urinary azelaic acid can be used to monitor renal function noninvasively in DM and DN patients. Our results identified markers of AKI on DM and the chronic progression of DN. In addition, the progression of DN was associated with AKI-like episodes occurring in DM.

Aerobic exercise attenuates high-fat diet–induced renal injury through kidney metabolite modulation in mice

“…Five of the 18 major kidney metabolites that we identified have previously been reported to be correlated with obesity-related metabolic dysregulation through previous studies [ 18–24 ]: indoleacrylic acid, azelaic acid, N-acetylglycine, 4-methylcatechol, and desoxycortone ( Table 2 , top 5). The first four of these were increased in the HFD-Ex group compared to the HFD group.…”

“…The first four of these were increased in the HFD-Ex group compared to the HFD group. Indoleacrylic acid is reported to lower LDL levels and improve immune-inflammatory responses, and it has been reported to be increased during the recovery of kidney diseases [ 18 ]. Patients with renal function decline show a decrease in azelaic acid [ 18 , 19 ].…”

“…Indoleacrylic acid is reported to lower LDL levels and improve immune-inflammatory responses, and it has been reported to be increased during the recovery of kidney diseases [ 18 ]. Patients with renal function decline show a decrease in azelaic acid [ 18 , 19 ]. Azelaic acid has been shown to positively rebalance plasma glucose, triglycerides, insulin, and markers for liver and kidney function to near normal levels as well as decrease the levels of lipid peroxidation markers in mice fed an HFD [ 20 ].…”

Use of ultra high performance liquid chromatography with high resolution mass spectrometry to analyze urinary metabolome alterations following acute kidney injury in post-cardiac surgery patients

“…Urine can contain the whole end products of renal metabolism; thus, the urinary metabolome has been used to predict the development of diabetic nephropathy [28] , [29] and evaluate the impact of AKI on different developmental stages of preterm neonates and the degree of renal injury under environmental exposure [30] . In this study, we performed the untargeted metabolomics of urine samples collected from a cohort of patients with AKI after cardiac surgery at different time points.…”