Abstract

Background: Carbamylation in stage-3 chronic kidney disease (CKD) distorts hemoglobin A1c (HbA1c) independently of glycemia, producing clinically relevant HbA1c–glucose discordance in type 2 diabetes (T2D). Objective: To develop and validate a carbamylation-corrected HbA1c index (CCHI) using chemically quantified homocitrulline and carbamylated albumin and to test whether correction improves agreement with glucose-anchored estimates. Methods: In a prospective, single–centre case–control study, adults with T2D and stage-3 CKD (n=25) were compared with T2D controls with preserved kidney function (n=25). Participants completed a seven-day, seven-point capillary glucose profile. HbA1c was measured by IFCC-aligned HPLC; homocitrulline by targeted liquid chromatography–tandem mass spectrometry (LC–MS/MS); and carbamylated albumin by Enzyme-Linked Immunosorbent Assay (ELISA). A multivariable linear model derived Carbamylation-Corrected HbA1c Index (CCHI) in controls; validation in CKD assessed reduction in absolute HbA1c–glucose discordance, agreement by Bland–Altman, and reclassification versus glucose-predicted categories. Results: Assays met goals, including HbA1c within-laboratory CVs 1.66% and 1.38% and excellent LC–MS/MS linearity for homocitrulline. In controls, homocitrulline and carbamylated albumin showed small, non-significant positive associations with HbA1c (R²=0.11185; F=1.4408; p=0.2581). In CKD, CCHI contracted absolute HbA1c–glucose discordance from a median 0.52% (IQR 0.40–0.66) to 0.19% (0.13–0.27) with Wilcoxon p=5.96×10⁻⁸. Agreement improved with Bland–Altman bias shrinking from +0.58% to +0.24%. Reclassification using glucose-predicted categories was favourable (net reclassification improvement 0.32; integrated discrimination improvement 0.046), while mean glucose was similar between cohorts, but variability was higher in CKD. Conclusions: Direct quantification of carbamylation and a simple correction restore concordance between HbA1c and glucose exposure in T2D. CCHI reduces residual error, tightens agreement, and improves clinical interpretation, offering a practical path to mitigate carbamylation-related bias in routine laboratories.