The Impact of Carbamylation and Anemia on HbA1c’s Association With Renal Outcomes in Patients With Diabetes and Chronic Kidney Disease

Abstract

OBJECTIVE Glycated hemoglobin (HbA1c) can predict risk for microvascular complications in patients with diabetes. However, HbA1c’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 HbA1c 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 HbA1c 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 m2, mean HbA1c was 7.5% (58 mmol/mol), and median C-Alb was 8.4 mmol/mol. HbA1c was lower in the higher C-Alb quartiles. During a median follow-up of 6.9 years, 763 participants experienced CKD progression. Overall, higher HbA1c was associated with an increased risk of CKD progression (adjusted hazard ratio 1.07 [95% CI 1.02–1.13]). However, using stratified analyses, HbA1c 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 HbA1c and CKD progression (P-interaction = 0.025). CONCLUSIONS In patients with coexisting diabetes and CKD, the association between HbA1c and CKD progression is modified by carbamylation and anemia. ARTICLE HIGHLIGHTS HbA1c’s reliability in chronic kidney disease (CKD) has been questioned, with concerns including competition between carbamylation and glycation and anemia affecting glycation accumulation. We investigated whether carbamylation and anemia modify the impact of HbA1c on renal outcomes in patients with diabetes and CKD. In 1,516 participants from the Chronic Renal Insufficiency Cohort (CRIC) study with diabetes and CKD, we found that the association between HbA1c and CKD progression was significantly diminished in patients with high carbamylation levels or presence of anemia. This finding may explain why HbA1c is less reliable in patients with CKD compared with the general population with diabetes.

Age-related markers and predictors of diabetic kidney disease progression in type 2 diabetes patients: a retrospective cohort study

“…This finding reinforces what has been documented in the medical literature, where cardiovascular diseases emerge as the primary cause of morbidity and mortality in individuals with T2D. 48 …”

Analytical performance evaluation of the Mindray enzymatic assay for hemoglobin A1c measurement

“…In addition, the bias of the results of four common hemoglobin variants (Hb S, Hb C, Hb D, and Hb E) did not exceed the permitted range. This demonstrates that enzymatic methods are less susceptible to interference from hemoglobin variants than ion-exchange high-performance liquid chromatography, as previously reported 14 . The enzymatic assay is based on measuring the percentage of HbA 1c in total hemoglobin.…”

“…HbA 1c is a product formed when hemoglobin and glucose combine in red blood cells. Therefore, any factors that cause changes in the quantity and quality of hemoglobin, such as hemoglobinopathies, derived hemoglobin, abnormalities in the erythrocyte survival lifespan, and drugs, can interfere with the HbA 1c assay [13][14][15][16] . Our results indicated that routine interferences such as lipemia, hemolysis, jaundice, and vitamin C did not affect the BS-600M enzymatic assay.…”

Prevalence of Diabetic Kidney Disease with Different Subtypes in Hospitalized Patients with Diabetes and Correlation Between eGFR and LncRNA XIST Expression in PBMCs

“…eGFR is known to be critical to the diagnosis and progression of DKD. Higher HbA1c was associated with an increased risk of CKD progression in patients with diabetes and remained an independent risk factor for adverse renal outcomes in patients with diabetes and CKD in patients with low carbamylation levels and no anemia [ 31 ]. According to a systematic review and meta-analysis of 20 cohorts, when HbA1c increased by 1%, the risk for DKD increased by 17% [ 32 ].…”