Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide

What was studied?

The study investigated the relationship between kidney function and circulating levels of trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite that has been implicated in increased cardiovascular risk. The researchers aimed to identify the primary factors influencing serum TMAO levels, with a particular focus on the modifiable role of kidney function. They employed a combination of machine learning, epidemiological analysis, and preclinical experiments to explore this relationship and assess whether kidney function not only regulates TMAO levels but is also affected by them, particularly in the context of kidney fibrosis.

Who was studied?

The study involved a cohort of 1,741 adult Europeans from the MetaCardis study, which included participants across a spectrum of cardiometabolic disease severity, ranging from metabolically healthy individuals to those with metabolic syndrome, type-2 diabetes (T2D), and ischemic heart disease (IHD). The cohort was representative of a European population, with individuals recruited from Denmark, France, and Germany. The study also included specific sub-cohorts such as the MetaCardis Body Mass Index Spectrum subset (BMIS), which focused on overweight or obese individuals presenting with features of metabolic syndrome but without overt T2D or ischemic heart disease.

What were the most important findings?

Kidney Function as the Primary Modifiable Factor Influencing TMAO Levels: The study identified kidney function, measured by estimated glomerular filtration rate (eGFR), as the most significant modifiable factor regulating fasting serum TMAO levels. Lower eGFR, indicative of reduced kidney function, was strongly associated with higher circulating TMAO levels.

Modest Impact of Diet and Gut Microbiota: While diet and gut microbiota composition were found to contribute to circulating TMAO levels, their impact was relatively modest compared to kidney function. The habitual intake of TMAO precursors like red meat and eggs did not significantly correlate with TMAO levels in the study’s non-interventional settings.

Bidirectional Relationship Between TMAO and Kidney Function: The study suggested a bidirectional relationship where impaired kidney function leads to higher TMAO levels, and elevated TMAO levels, in turn, contribute to kidney damage, particularly fibrosis. This was corroborated by preclinical models showing that TMAO exposure increases kidney scarring.

Therapeutic Implications of Reno-Protective Drugs: Patients with T2D who were receiving glucose-lowering drugs with reno-protective properties, specifically GLP-1 receptor agonists (GLP-1RAs), had significantly lower circulating TMAO levels compared to matched controls. This finding suggests that reno-protective medications could potentially be used to lower TMAO levels and mitigate associated cardiovascular risks.

What are the greatest implications of this study?

Clinical Management of Cardiovascular Risk: The study highlights the critical role of kidney function in managing cardiovascular risk associated with elevated TMAO levels. It suggests that preserving or improving kidney function could be a key strategy in reducing circulating TMAO levels and, by extension, cardiovascular risk.

Potential for Therapeutic Interventions: The findings imply that reno-protective therapies, particularly those involving GLP-1 receptor agonists, could have a dual benefit in patients with T2D or other cardiometabolic conditions: improving kidney function and lowering TMAO levels. This could lead to novel therapeutic strategies aimed at reducing TMAO-related cardiovascular risk.

Reevaluation of Dietary and Microbiota Interventions: While diet and gut microbiota composition have been previously considered major contributors to TMAO levels, this study suggests that in the context of non-interventional settings, their impact may be secondary to that of kidney function. This could shift the focus of future research and clinical practice towards targeting kidney health as a more effective means of controlling TMAO levels.

Mechanistic Insights into TMAO and Kidney Health: The Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide study provides mechanistic insights into how TMAO contributes to kidney damage, particularly through the promotion of renal fibrosis. This understanding could inform future research into the development of targeted therapies that specifically address the pro-fibrotic effects of TMAO in kidney disease.