Untargeted metabolomics reveals N, N, N-trimethyl-L-alanyl-L-proline betaine (TMAP) as a novel biomarker of kidney function

Abstract

The diagnosis and prognosis of chronic kidney disease (CKD) currently relies on very few circulating small molecules, which can vary by factors unrelated to kidney function. In end-stage renal disease (ESRD), these same small molecules are used to determine dialysis dose and dialytic clearance. Therefore, we aimed to identify novel plasma biomarkers to estimate kidney function in CKD and dialytic clearance in ESRD. Untargeted metabolomics was performed on plasma samples from patients with a single kidney, non-dialysis CKD, ESRD and healthy controls. For ESRD patients, pre- and post-dialysis plasma samples were obtained from several dialysis modalities. Metabolomics analysis revealed over 400 significantly different features in non-dialysis CKD and ESRD plasma compared to controls while less than 35 features were significantly altered in patients with a single kidney. N,N,N-trimethyl-L-alanyl-L-proline betaine (TMAP, AUROC = 0.815) and pyrocatechol sulfate (AUROC = 0.888) outperformed creatinine (AUROC = 0.745) in accurately identifying patients with a single kidney. Several metabolites accurately predicted ESRD; however, when comparing pre-and post-hemodialysis, TMAP was the most robust biomarker of dialytic clearance for all modalities (AUROC = 0.993). This study describes TMAP as a novel potential biomarker of kidney function and dialytic clearance across several hemodialysis modalities.

Plasma Metabolomic Signatures of Chronic Obstructive Pulmonary Disease and the Impact of Genetic Variants on Phenotype-Driven Modules

“…The lone metabolite associated with exacerbation frequency, of TMAP, further exemplifies the potential systemic effects of COPD. Although the reported association is novel in COPD, TMAP was recently identified as a biomarker of chronic kidney disease, 68 a comorbidity of COPD, 69 with a similar inverse association between TMAP abundances and disease severity. Moreover, while the biologic origin of TMAP has not yet been identified, it is suggested that myosin light-chain (MLC) protein degradation results in the release of TMAP.…”

“…Moreover, while the biologic origin of TMAP has not yet been identified, it is suggested that myosin light-chain (MLC) protein degradation results in the release of TMAP. 68 Disruption in MLC isoforms has been observed in COPD subjects with reduced activity and low oxygen supply, yet further work is needed to understand the pathophysiology of TMAP in exacerbations.…”

Urinary metabolic phenotyping for Alzheimer’s disease

“…In addition, observed here N,N,N -trimethyl- l -alanyl- l -proline betaine is a recently discovered plasma biomarker of kidney function. Plausibly this metabolite is a product of betaine and myosin light chain degradation 70 , though this hypothesis has yet to be confirmed. Another detected product of gut microbiota processes is butyrylcarnitine—a product of l -carnitine processing in the human body.…”

Combined Metabolic Activators Reduces Liver Fat in Nonalcoholic Fatty Liver Disease Patients

“…We also found that the plasma level of N,N,N-trimethyl-alanylproline betaine (TMAP) was significantly downregulated in the CMA group on Day 70, even after weight loss adjustment (Figure 3C, Datasets S6), as were creatinine levels (Figure 1F, Table 1, Dataset S4). TMAP has been described as a novel potential biomarker of the dialytic clearance that can accurately define kidney function (Velenosi et al, 2019).…”