Homocitrulline Is Associated with Cardiovascular Outcomes in Nondialysis Patients with CKD

Abstract

Key Points:

1. In nondialysis CKD, baseline serum homocitrulline was positively and independently linked to age, low eGFR, urea, anemia, and diuretics.

2. A higher serum homocitrulline concentration was associated with an elevated risk of major adverse cardiovascular event and all-cause mortality rate.

3. Targeting elevated levels of protein carbamylation may be a way of modifying the cardiovascular risk in patients with CKD.

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

Methods: CKD-renal epidemiology and information network is a prospective cohort of patients with CKD and an eGFR <60 ml/min per 1.73 m². The baseline serum HCit concentration was centrally measured. The 2195 patients included in the analysis were divided into tertile (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 for the first major adverse cardiovascular event (MACE) and death before KRT.

Results: Among the 2195 included patients, the median age was 68 years and the mean eGFR was 34.6 ml/min per 1.73 m². The median (interquartile range) 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 hazard ratio (95% confidence interval) for MACEs as a function of the baseline HCit concentration was 1.32 (0.96 to 1.84) for T2 and 1.63 (1.16 to 2.30) for T3, compared with T1. The risk of death before KRT as a function of the baseline serum HCit concentration was 2.09 (1.45 to 3.03) for T3 and 1.48 (1.04 to 2.11) for T2, compared with 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.

Clinical Trial registry name and registration number:: NCT03381950.

Keywords: CKD; cardiovascular; cardiovascular disease; cardiovascular events; kidney failure.

Graphical abstract

Figure 1

Serum HCit concentrations, by CKD stage. HCit, homocitrulline; Lys, lysine.

Figure 2

Numbers of events, incidence rates, and adjusted HRs for MACEs (whether atheromatous or nonatheromatous and fatal or nonfatal) and death before KRT as a function of the baseline serum HCit concentration. *HRs were adjusted for age, sex, smoking status, body mass index, diabetes, systolic blood pressure, estimated glomerular filtration rate, urine albumin- or protein-to-creatinine ratio (natural log-transformed), ACR estimated from proteinuria (binary variable), history of CVD, anemia, serum albumin, high-sensitivity C-reactive protein (natural log-transformed), and the use of diuretics, statins, and antithrombotic agents at baseline. ACR, albumin-to-creatinine ratio; CVD, cardiovascular disease; HR, hazard ratio; MACE, major adverse cardiovascular event.

Figure 3

Adjusted HR for the occurrence of the first MACE and death before KRT, as a function of the baseline serum HCit concentration, using penalized spline terms. (A) Adjusted HR for first MACE, as a function of the baseline serum HCit concentration. (B) Adjusted HR for death before KRT, as a function of the baseline serum HCit concentration. CI, confidence interval.