Introduction Glycohemoglobin (A1c) levels are a widely accepted proxy measure of blood glucose control in patients with diabetes. Significant clinical decision making, as well as evaluation of “quality” for pay-for-performance by insurers, are based upon A1c. Target levels range from less than 6.5 to less than 8, depending upon the source of the guidelines. 1 However, in certain cases, A1c does not correlate to mean blood glucose level. Any condition that alters erythrocyte (RBC) survival can adversely affect this correlation. 2-6 One of these conditions is chronic kidney disease (CKD), a common complication of uncontrolled diabetes. Thus, in some of the patients for whom an accurate measure of glycemic control is most important, A1c is unreliable. Glycation of Hemoglobin Hemoglobin (Hb) undergoes glycation as a result of exposure to reducing sugars in the blood. Glycation is the non-enzymatic process of bonding glucose or fructose to a protein. Unlike true glycosylation (the enzyme-mediated binding of sugars to proteins, necessary for their proper functioning), the addition of these moieties via glycation is haphazard, not occurring at specifically defined sites on the molecule. This process occurs via a slow reaction that is only slightly reversible. 7 The degree of glycation increases in relation to the level of sugar in the blood and in relation to the age of the RBC in which the Hb is located. 7 There is variation in glycation rates between individuals. 8,9 This linear relationship related to both mean blood glucose level and RBC age means that a high A1c level correlates to high mean blood glucose levels, as seen in diabetes, but also correlates to longer RBC survival as can be seen in B 12 and folate deficiencies. Conversely, shortened average RBC age – as seen in conditions such as sickle cell disease, G6PD-deficiency and other hemolytic conditions – yields an A1c level that is lower than would be predicted by the mean glucose levels. 4,10 Interestingly, elevated A1c levels by themselves shorten RBC survival – by seven days for every 1 percent increase in A1c – so that high glycation of Hb may result in para- doxical artificial lowering of A1c levels, relative to mean blood glucose. 11 Table 1 presents some of the conditions which may affect A1c levels. 59 February 2013 Journal When 7 isn’t 7: Glycohemoglobin and Chronic Kidney Disease By Mark Oppenheimer, MD; Richard Jensen, MD; and Mark K. Huntington, MD, PhD Abstract Glycohemoglobin level (A1c) is widely viewed as the gold standard for assessing glycemic control. Clinical decisions are based upon it, and reimbursement is increasingly tied to it. However, there are a number of conditions which result in loss of correlation between A1c and mean blood glucose levels. Chronic kidney disease (CKD) is one condition, prevalent as a comorbidity with diabetes, that can result in an inaccurate impression of glycemic control based on measured A1c levels. We review the glycation of hemoglobin, how it is affected in CKD, and review alternative methods for the assessment of glycemic control in these patients. Factor Effect on Measured A1c Decreased Mean RBC Age Decreased RBC Survival G6PD deficiency Sickle cell Artificially low Hb glycation Hemolysis Increased Erythropoeisis Erythropoeitin Increased Mean RBC Age B12 deficiency Artificially high Folate deficiency Glycation Phenotype (high/low) Artificially high/low Table 1. The Effect of Various Factors on the Relationship of Measured A1c to Mean Glucose Concentrations