Association of plasma ceramide with decline in kidney function in patients with type 2 diabetes

Abstract

Circulating ceramide levels are dysregulated in kidney disease. However their associations with rapid decline in kidney function (RDKF) and end-stage kidney disease (ESKD) in patients with type 2 diabetes (T2D) are unknown. In this prospective study of 1746 T2D participants, we examined the association of plasma ceramide Cer16:0, Cer18:0, Cer24:0 and Cer24:1 with RDKF, defined as an estimated glomerular filtration rate (eGFR) decline of 5ml/min/1.73m2/yr or greater, and ESKD defined as eGFR <15/min/1.73m2 for at least three months, on dialysis, or renal death at follow-up. We performed multivariable logistic and cox regression analyses adjusted for traditional cardio-renal risk factors, including baseline renal functions. During a median (interquartile range) follow-up period of 7.7 (4.7-8.9) years, 197 (11%) patients experienced RDKF. Ceramide Cer24:0 (odds ratio [OR]=0.71, 95%CI 0.56-0.90) and ratios Cer16:0/Cer24:0 (OR=3.54, 95%CI 1.70-7.35), Cer18:0/Cer24:0 (OR=1.89, 95%CI 1.10-3.25) and Cer24:1/Cer24:0 (OR=4.01, 95%CI 1.93-8.31) significantly associated with RDKF in multivariable analysis. 124 patients developed ESKD. The ratios Cer16:0/Cer24:0 (hazard ratio [HR]=3.10, 95%CI 1.44-6.64), and Cer24:1/Cer24:0 (HR=4.66, 95%CI 1.93-11.24) significantly associated with a higher risk of ESKD. The Cer24:1/Cer24:0 ratio improved risk discrimination for ESKD beyond traditional risk factors by small but statistically significant margin (Harrell C-index difference 0.01; P=0.022). A high ceramide risk score, constructed using individual ceramide level and ceramide ratios, also associated with RDKF (OR=2.28, 95%CI 1.26-4.13) compared to lower risk score. In conclusion, specific ceramide levels and their ratios are associated with RDKF and conferred an increased risk of ESKD, independently of traditional risk factors in patients with T2D.