The association between TMAO, CMPF, and clinical outcomes in advanced chronic kidney disease: results from the European QUALity (EQUAL) Study

Abstract

Background Trimethylamine N-oxide (TMAO), a metabolite from red meat and fish consumption, plays a role in promoting cardiovascular events. However, data regarding TMAO and its impact on clinical outcomes are inconclusive, possibly due to its undetermined dietary source. Objective We hypothesized circulating TMAO derived from fish intake might cause less harm compared to red meat source by examining the concomitant level of 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), a known biomarker of fish intake, and investigated the association between TMAO, CMPF and outcomes. Design Patients were recruited from the European QUALity study on treatment in advanced CKD (EQUAL) among individuals ≥65 years whose eGFR had dropped for the first time to ≤20mL/min/1.73m2 during last 6 months. The association between TMAO, CMPF and outcomes including all-cause mortality and kidney replacement therapy (KRT) was assessed among 737 patients. Patients were further stratified by median cut-offs of TMAO and CMPF, suggesting high/low red meat and fish intake. Results During a median of 39 months’ follow-up, 232 patients died. Higher TMAO was independently associated with an increased risk of all-cause mortality (multivariable-hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.17, 1.83). Higher CMPF was associated with a reduced risk of both all-cause mortality (HR 0.79, 95%CI 0.71, 0.89) and KRT (HR 0.80, 95%CI 0.71, 0.90), independent of TMAO and other clinically relevant confounders. In comparison to patients with low TMAO and CMPF, patients with low TMAO and high CMPF had reduced risk of all-cause mortality (adjusted HR 0.49, 95% CI 0.31, 0.73), whereas those with high TMAO and high CMPF showed no association across adjusted models. Conclusions High CMPF conferred an independent role in health benefits and might even counteract the unfavorable association between TMAO and outcomes. Whether higher circulating CMPF are due to fish consumption, and/or CMPF is a protective factor remains to be verified.

Role of the Microbiome in Gut-Heart-Kidney Cross Talk

“…The gut microbiota and their metabolism and effect on the intestinal barrier function are an interesting target as they are at the origin of toxin generation and especially of those uremic toxins that have been associated with worse overall and cardiovascular outcome in CKD. 10,11 To develop a systems biology view of gut-heart-kidney interactions, we apply the conceptual framework of the remote sensing and signaling theory. This theory focuses on remote small-molecule communication across inter-organ axes (eg, gut-brain, gut-heart-kidney, and gut-liver-kidney).…”

“…The gut microbiota and their metabolism and effect on the intestinal barrier function are an interesting target as they are at the origin of toxin generation and especially of those uremic toxins that have been associated with worse overall and cardiovascular outcome in CKD. 10,11…”

Consumption of Fish in Chronic Kidney Disease – A Matter of Depth

“…[19] A prospective study of 824 older patients with CKD stage 4 recruited from the European QUALity Study (EQUAL Study) showed that high TMAO levels in combination with low levels of 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), a metabolite of furan fatty acids that reflect the intake of fish, were independently associated with an increased risk of all-cause mortality and shorter time until the start of renal replacement therapy. [20] When interpreting these data, the reduced renal excretion of TMAO [13] and the observation that loop diuretics [21] decrease the renal elimination rate of TMAO must be considered. Thus, patients with CKD and/or on loop diuretics may be more susceptible to a regular intake of deep-sea fish with high muscular TMAO content.…”

Trimethylamine-N-oxide: a potential biomarker and therapeutic target in ischemic stroke

“…The above phenomena are possibly due to overlapping risk factors among patients with ischemic stroke. Patients with cardioembolic stroke also suffer from hypertension (26), diabetes (27,28), renal insufficiency (29)(30)(31), and coronary artery disease (32), disorders that can all lead to elevated plasma TMAO concentrations, resulting in smaller differences in plasma TMAO levels among stroke patients with different etiologies. Xu et al (33) found drastically higher plasma TMAO levels in stroke patients in the LAA group and CE (Cardioembolic) group than in the control group, speculatively pointing to TMAO as crucial to the pathophysiology of atherosclerosisrelated stroke and suggesting that the increase in TMAO levels in the CE group was probably associated with the ability of TMAO to promote platelet hyperresponsiveness and heighten the risk of thrombosis (34).…”