Homocitrulline is Associated with Cardiovascular Outcomes in Non-Dialysis Patients with CKD.

Abstract

Background: Protein carbamylation contributes to an increase in the cardiovascular risk in certain patient populations (e.g. in patients with chronic kidney disease (CKD) because of elevated urea concentrations). Homocitrulline (HCit) is a biomarker of overall protein carbamylation. In a study of a large cohort of non-dialysis patients with a confirmed diagnosis of CKD and an estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2, we sought to determine whether the serum HCit concentration was associated with adverse cardiovascular outcomes and all-cause mortality.

Methods: CKD-REIN is a prospective cohort of CKD patients with an eGFR<60mL/min/1.73m2. The baseline serum HCit concentration was centrally measured. The 2,195 patients included in the analysis were divided into tertiles (T) groups according to the baseline HCit concentration (T1<292, T2=[292-429], and T3≥430 µmol/mol lysine). Adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) for the first major adverse cardiovascular event (MACE) and death before kidney replacement therapy (KRT).

Results: Among the 2,195 included patients, the median age was 68, and the mean eGFR was 34.6 mL/min/1.73m2. The median [IQR] serum HCit was 352[266-481] µmol/mol lysine. The HCit concentration was correlated with the eGFR (r=-0.57) and the urea concentrations (r=0.73). In an adjusted linear regression model, the HCit concentration was independently and positively associated with age, eGFR decrease, urea, anemia, baseline prescription of diuretics, and negatively associated with male sex and an elevated urinary albumin-to-creatinine ratio. The adjusted HR[95%CI] for MACEs as a function of the baseline HCit concentration was 1.32[0.96-1.84] for T2 and 1.63[1.16-2.30] for T3, compared to T1. The risk of death before KRT as a function of the baseline serum HCit concentration was 2.09[1.45-3.03] for T3 and 1.48[1.04-2.11] for T2, compared to T1.

Conclusions: Our analysis of a large cohort of patients with CKD demonstrated that the serum HCit concentration was associated with a greater likelihood of a MACE and death. To confirm causality, further studies of therapeutic interventions for preventing or reducing carbamylation are now warranted.