Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study

Abstract

Background: Metabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis. Methods: We examined the association between blood metabolites and CKD progression, defined as the subsequent development of end-stage renal disease (ESRD) or estimated glomerular filtrate rate (eGFR) halving, in 1773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African American Study of Kidney Disease and Hypertension (AASK), and 5305 participants of the Atherosclerosis Risk in Communities (ARIC) study. Results:In CRIC, more than half of measured metabolites were associated with CKD progression in minimally adjusted Cox proportional hazards models, but the number and strength of associations were markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten metabolites were significantly associated with CKD progression in fullyadjusted models in CRIC; three of these metabolites were also significant in fully-adjusted models in AASK and ARIC, highlighting potential markers of glomerular filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), and azotemia (homocitrulline).Our findings also nominate N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC. Conclusion:Together, our findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression.

Canagliflozin attenuates kidney injury, gut-derived toxins, and gut microbiota imbalance in high-salt diet-fed Dahl salt-sensitive rats

“…After intestinal microflora reconstruction by canagliflozin, these toxic metabolites (methyhistidines, creatinine, and homocitrulline) were significantly reduced in serum, thus alleviating renal injury caused by the HSD. Similar clinical studies have shown that these measured metabolites, including tryptophan-derived uremic toxins (indoxyl sulfate) and metabolites involved in histamine metabolism (methyhistidines), and azotemia (homocitrulline), are associated with CKD progression [ 50 , 51 ]. The main functions of the activity appear to be altered monocyte activation, intensified inflammatory processes, and augmented oxidative stress by these uremic toxins [ 52 ].…”

N-acetylaspartate from fat cells regulates postprandial body temperature

“…Limitations of our study include the fact that we do not rule out the possibility that NAA synthesis and disposal occurs elsewhere to regulate the whole-body pyrimidine pool. N-acetylated amino acids undergo glomerular filtration and reabsorption in the proximal tubule where they are hydrolyzed by aminoacylase 1 37 . ASPA expression also occurs in the kidney, though its role there remains uncharacterized.…”

Integrated NMR and MS Analysis of the Plasma Metabolome Reveals Major Changes in One-Carbon, Lipid, and Amino Acid Metabolism in Severe and Fatal Cases of COVID-19

“…For instance, gluconic acid has been previously linked to hyperglycemia and brain injury in ischemic stroke [ 53 ], and it may be considered a marker of oxidative stress. Additionally, N -acetylation of amino acids, including the formation of N -acetylserine, has been associated with SARS-CoV-2 infection and COVID-19 pathogenesis [ 54 ], whereas higher levels of N -acetylserine have been recently considered a marker of the progression of chronic kidney disease [ 55 ]. Our data, built on these previous observations, highlights an association between these metabolic alterations and poor outcomes in a cohort of ICU-admitted patients.…”