The Impact of Carbamylation and Anemia on HbA(1c)’s Association With Renal Outcomes in Patients With Diabetes and Chronic Kidney Disease

OBJECTIVE: Glycated hemoglobin (HbA(1c)) can predict risk for microvascular complications in patients with diabetes. However, HbA(1c)’s reliability in chronic kidney disease (CKD) has been questioned, with concerns including competition from another posttranslational protein modification, carbamylation, acting on the same amino groups as glycation, and anemia with reduced erythrocyte lifespans leading to altered glycation accumulation. We investigated whether carbamylation and anemia modify the impact of HbA(1c) on renal outcomes in patients with diabetes and CKD. RESEARCH DESIGN AND METHODS: In 1,516 participants from the Chronic Renal Insufficiency Cohort study with diabetes and CKD, Cox regression models were applied to evaluate the association between HbA(1c) and CKD progression (composite of end-stage kidney disease or 50% decline in estimated glomerular filtration rate [eGFR]), stratified by carbamylated albumin (C-Alb) quartiles and anemia. RESULTS: The mean eGFR was 38.1 mL/min/1.73 m(2), mean HbA(1c) was 7.5% (58 mmol/mol), and median C-Alb was 8.4 mmol/mol. HbA(1c) was lower in the higher C-Alb quartiles. During a median follow-up of 6.9 years, 763 participants experienced CKD progression. Overall, higher HbA(1c) was associated with an increased risk of CKD progression (adjusted hazard ratio 1.07 [95% CI 1.02–1.13]). However, using stratified analyses, HbA(1c) was no longer associated with CKD progression in the highest C-Alb quartile, but did show a monotonic increase in CKD progression risk across each lower C-Alb quartile (P-interaction = 0.022). Anemia also modified the association between HbA(1c) and CKD progression (P-interaction = 0.025). CONCLUSIONS: In patients with coexisting diabetes and CKD, the association between HbA(1c) and CKD progression is modified by carbamylation and anemia.