Novel biomarkers, homocitrulline and carbamylated albumin, promising in predicting chronic kidney disease risk: Study

The study revealed similar carbamylated albumin (C-Alb) and homocitrulline (HCit, carbamylated lysine) performances across multiple prognostic assessments. The markers appear readily comparable in CKD epidemiological studies.

"C-Alb and HCit perform similarly with regards to associations with important clinical endpoints in a large CKD cohort," the researchers wrote. "The markers also show similar reclassification and risk discrimination measures when looking at clinical outcomes."

Homocitrulline, a product of homocysteine carbamylation, and carbamylated albumin, formed by the non-enzymatic modification of albumin by cyanate, have emerged as promising indicators of protein carbamylation, a process implicated in CKD pathogenesis. By measuring levels of these circulating markers, researchers were able to more accurately stratify individuals based on their risk of developing CKD.

Against the above background, Sahir Kalim, Harvard Medical School, Boston, MA, USA, and colleagues aimed to compare the prognostic utility of these two markers to facilitate comparisons of existing studies employing either marker alone and to inform future carbamylation studies.

For this purpose, the researchers assayed serum C-Alb and free HCit levels from the same time point in 1632 individuals with CKD stages 2–4 enrolled in the prospective Chronic Renal Insufficiency Cohort (CRIC) study. Adjusted Cox proportional hazard models assessed risks for the outcomes of death (primary) and end-stage kidney disease (ESKD) using each marker. Each marker's prognostic value was compared using C-statistics, net reclassification improvement, and integrated discrimination improvement.

The study led to the following findings:

· Participant demographics included a mean age of 59 years, 43% were females.

· C-Alb and HCit levels were positively correlated with one another (Pearson correlation coefficient 0.64).

· Higher C-Alb and HCit levels showed a similar increased risk of death (e.g., the adjusted hazard ratio [HR] for death in the 4th carbamylation quartile compared to the 1st was 1.90 for C-Alb, and 1.89 for HCit; and on a continuous scale, the adjusted HR for death using C-Alb was 1.24 per standard deviation increase, and 1.27 using HCit).

· Both biomarkers also had similar HRs for ESKD.

· The C-statistics were similar when adding each carbamylation biomarker to base models (e.g., for mortality models, the C-statistic was 0.725 with C-Alb and 0.725 with HCit, compared to a base model 0.723).

· There were similarities between the net reclassification improvement and integrated discrimination improvement metrics.

"To this end, it appears that HCit and C-Alb are both reasonable markers to employ in carbamylation-related studies and could be comparable to one another across studies acknowledging the observed differences reported herein," the researchers concluded. The many clinical studies with existing metabolomic data, including HCit could be readily analyzed to answer research questions specific to carbamylation.

"There will be a need for future work to establish if the markers are superior when looking at specific clinical applications."

Reference:

Awwad, A., Rhee, E.P., Grams, M. et al. Comparative CKD risk prediction using homocitrulline and carbamylated albumin: two circulating markers of protein carbamylation. BMC Nephrol 25, 185 (2024). https://doi.org/10.1186/s12882-024-03619-6