Methylamine metabolites and progression to kidney failure in type 2 diabetes: An Asian and European prospective study

Unlike trimethylamine N-oxide (TMAO), the role of methylamine pathway metabolites in diabetic kidney disease (DKD) remains unclear. We investigated the association of circulating methylamines with progression of DKD in a prospective cohort study of patients with type 2 diabetes of two different ethnic backgrounds.

We analyzed two independent cohorts: a European-origin cohort (SURDIAGENE France; n = 1,357) and an Asian-origin cohort (Khoo Teck Puat Hospital-DKD [KTPH-DKD] Singapore, n = 1,868). The primary composite renal outcome in SURDIAGENE was sustained doubling of serum creatinine or kidney failure with replacement therapy (KFRT), while the secondary outcome was 40% renal function loss (RFL40). In KTPH-DKD, KFRT was the primary outcome. Baseline betaine, carnitine, choline, trimethylamine and TMAO concentrations were measured in plasma by mass-spectrometry. Cox regression models were used to estimate the risk of DKD progression, adjusting for demographics, clinical parameters, and comorbidities.

Over a median follow-up of 7.1 years (IQR 4.5-10.7), we registered 75 composite renal outcomes in SURDIAGENE and over 10.7 years (IQR 7.0-11.8), 149 KFRT in KTPH-DKD. Choline was the only consistently associated with progression of DKD in both cohorts: HR [95%CI] per 1 SD = 1.29 [1.02;1.62], P = 0.033 for composite renal outcome, 1.11 [1.01;1.23], P = 0.028 for RFL40 in SURDIAGENE, and 1.84 [1.30;2.61], P < 0.001 for KFRT in KTPH-DKD.

Plasma choline is an independent risk factor for DKD progression in two independent type 2 diabetes populations. Interventional trials are needed to assess whether reducing dietary choline intake could mitigate severe renal outcomes in type 2 diabetes.