Dissociation of Glycated Albumin and HbA1c Is Associated With a Decline of Glomerular Filtration Rate as Evaluated by Inulin Clearance

Hemoglobin A1c (HbA1c), microalbuminuria, and estimated glomerular filtration rate (eGFR) are widely used for assessment of diabetic kidney disease (DKD). However, we have shown that eGFR is inaccurate in DKD (1). Further, HbA1c has several limitations as a glycemic marker (2). Guidelines for hemodialysis patients in Japan recommend evaluation of glycemic control using glycated albumin (GA) rather than HbA1c, which is affected by conditions such as anemia and renal failure (3). Renal anemia is a common complication in chronic kidney disease (CKD), including in predialysis patients with CKD. Thus, we evaluated the correlations between GFR measured accurately by inulin clearance (Cin) and the dissociation of GA and HbA1c in nondialysis patients with CKD. The study protocol was approved by the Ethics Committee of Osaka City University Graduate School of Medicine (#3506) as an opt-out study. The study was performed between January 2009 and March 2020 at Osaka City University Hospital. The subjects were 133 patients (60.6 ± 12.5 years, 66 males) with glycemic disorder. Diagnosis of type 2 diabetes (87 subjects) was based on a history of diabetes or criteria in the “Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus” (4). Prediabetes (46 subjects) was evaluated by a 2-h 75-g oral glucose tolerance test. The subjects were restricted to those with CKD stages 1–4. GFR was evaluated by the gold standard Cin, determined by the constant input clearance technique with inulin. Cin was calculated by the UinV/Pin method, where Uin is the urinary inulin concentration, V is the urinary volume, and Pin is the mean plasma inulin concentration from measurements at the beginning and end of the clearance period. GA was measured by an enzymatic method using a Lucica GA-L kit (Asahi Kasei Pharma Co., Tokyo, Japan). In single regression analyses (Fig. 1), there were significant positive correlations between GA and HbA1c in each stage of CKD evaluated by eGFR (CKD 1, r 5 0.890, P < 0.0001, slope 2.470; CKD 2, r 5 0.825, P < 0.0001, slope 2.460; CKD 3 or 4, r 5 0.718, P 5 0.0004, slope 2.208) and by Cin (CKD 1, r 5 0.891, P < 0.0001, slope 2.058; CKD 2, r 5 0.866, P < 0.0001, slope 2.447; CKD 3 or 4, r 5 0.830, P < 0.0001, slope 3.138). In advanced CKD stages evaluated by Cin (P 5 0.0024) but not by eGFR (P 5 0.6495), the regression slopes for GA and HbA1c were significantly steeper, as evaluated by analyses of covariance. The GA/ HbA1c ratio was significantly negatively correlated with eGFR (r 5 0.189, P 5 0.0302) and Cin (r 5 0.408, P < 0.0001). In multiple regression analysis using a model including Cin or eGFR as an independent variable, Cin (b 5 0.233, P 5 0.0097), but not eGFR (b 5 0.007, P 5 0.9415), was significantly associated with the GA/HbA1c ratio after adjustments for other clinical parameters. Association of the GA/HbA1c and eGFR/Cin ratios was also evaluated, as eGFR may be inaccurate in patients with DKD. eGFR/Cin (b 5 0.227, P 5 0.0023) was significantly associated with GA/HbA1c after adjustments for other clinical parameters. In this study, the GA/HbA1c ratio was higher in advanced CKD stages evaluated by Cin but not by eGFR, which is used in daily practice. Further, eGFR/Cin ratios were significantly associated with GA/ HbA1c ratios. The prevalence of anemia increases even in the early stage of kidney failure, particularly in diabetes (5).