Is HbA1c A Reliable Test In Patients With Diabetes And Renal Disease?

   Reportedly 23.6 million individuals in the United States (or 8 percent of the American population) are affected by diabetes.1 Many of those with diabetes will develop related comorbidities such as microvascular pathology in the retina, renal glomeruli and peripheral nerves. Other comorbidities include accelerated atherosclerotic microvascular disease affecting arteries that supply the heart, brain and lower extremities.2,3

   Controlled clinical trials in patients with type 2 diabetes have established that rigid glycemic control results in improved long-term outcomes and a decreased incidence of diabetic complications.4,5 Further, many studies have demonstrated a strong correlation among mean levels of glycemia, measured as glycated hemoglobin A1c (HbA1c), and diabetic complications.1

   Collectively, this body of knowledge provides the foundation for the recommended treatment goals from the American Diabetes Association (ADA) of maintaining HbA1c at less than 7%. However, only one-third of patients with diabetes achieve this goal and even less reach the target level of 6.5% HbA1c that the American College of Endocrinology promotes.2

   Other clinical evidence indicates favorable effects on cardiovascular disease in those with tight glycemic control. As we know, cardiovascular disease is a main cause of death in patients with diabetes. Strict glycemic control is reportedly a strong prognostic indicator for patients who have diabetes with chronic kidney disease (CKD) requiring hemodialysis.5

   Establishing the relationship between HbA1c and glycemic control in this group of individuals is essential because of the fact that almost half of all end-stage renal disease (ESRD) patients on dialysis in the U.S. are affected by diabetes. Unfortunately, few studies examine the association between HbA1c and clinical outcomes in the dialysis patient.3

   With these trends and considerations in mind, let us take a closer look at the reliability of HbA1c in patients with diabetes and renal disease.

What You Should Know About HbA1c

   Management of glycemic control is of utmost importance in all patients with diabetes. Currently, we diagnose diabetes by using fasting plasma glucose and the oral glucose tolerance test.6 Currently, researchers are looking at the measurement of glycated proteins.4 Glycated hemoglobin has became the mainstay of evaluating long-term glycemic management as both a screening and diagnostic tool, and appears to be on the brink of official recognition as the preferred diagnostic test for diagnosing diabetes.6

   We are already using this value for patient education and counseling, for feedback about diabetes control, to improve patient motivation and to monitor management.7 Measurement of HbA1c also aids in the evaluation of the risk of diabetic complications.8 Mitka notes the thoughts of the ADA, the European Association for the Study of Diabetes and the International Diabetes Federation proposing the use of HbA1c as the preferred diagnostic test for diabetes.6,9

   Although there is no international standard for determining HbA1c and various methods are available for its collection, strides continue toward creating a more standardized approach to its measurement.7 Typically, HbA1c is measured via high performance liquid chromatography and immunoassay.4,7 The percent HbA1c of glycated hemoglobin provides an estimation of blood glucose levels over a three- to four-month period.7 This laboratory test is favorable to previous methods due to its ease of use. Accordingly, this test may facilitate earlier diagnosis of patients with diabetes and potentially lead to fewer diabetes-associated complications.6

How Hemodialysis Complicates The Diagnostic Picture

   Hemoglobin A1c is the most widely used assay for evaluation of long-term glycemic control and is strongly correlated with adverse outcome risk. Moreover, the well established risks of diabetic microvascular and macrovascular complications are strongly associated with the HbA1c level in patients with both type 1 and type 2 diabetes. In general, a HbA1c <7% is associated with the projected reduction in diabetic complications over time.4 However, multiple studies have recently reported that HbA1c may not provide a relevant assay for glycemic control in hemodialysis patients.4,5,8

   Hemoglobin A1c is the product of chemical condensation of circulating hemoglobin that has reacted with glucose and thus is influenced by factors other than glucose alone.4,5 The uremic environment, blood loss during dialysis and frequent blood sampling contribute to the decreased life span of erythrocytes in those on hemodialysis.4 The HbA1c is also lower due to the reduced red blood cell survival, red blood cell transfusions and erythropoietin treatments in those on hemodialysis.4,5,8,9 It is important to realize that erythropoietin accelerates the production of new erythrocytes and the proportion of young erythrocytes in peripheral blood must increase after erythropoietin injection.5

   Additionally, these immature red blood cells have less glycemic exposure time for glycosylation to occur.5,8 The HbA1c levels are also theoretically suppressed by the resulting anemia associated with the shorter life span of erythrocytes. These factors establish the argument that HbA1c underestimates glycemic control in hemodialysis patients and that HbA1c is not a reliable test. Therefore, one should not use HbA1c as a guideline in patients with diabetes and renal disease who are on dialysis.3,4

   Uzu and colleagues stated that HbA1c levels are underestimated in hemodialysis patients, especially in correlation with low hematocrit and those treated with higher doses of erythropoietin.4 The study recommended a more accurate means to estimate glycemic control:

   • HbA1c x 1.14 if the hematocrit is ≥ 30%;
   • HbA1c x 1.19 if the hematocrit is < 30% and treated with low dosages of erythropoietin; and
   • HbA1c x 1.38 if hematocrit is < 30% and treated with high dosing of erythropoietin.

   In those undergoing maintenance hemodialysis, researchers have reported that higher HbA1c values are incrementally associated with a higher burden of microvascular complications and a higher risk of cardiovascular death.4 Fukuoka and co-workers found no significant association between HbA1c and survival in diabetic ESRD patients.8 Evaluating patients from a large national dialysis organization, Kalantar-Zadeh and colleagues found a higher mortality rate in those with lower HbA1c levels.3

Can Glycated Albumin Be An Alternative Marker For Glycemic Control In Patients With Diabetes?

   The lack of reliability in the HbA1c value in patients with diabetes and renal disease has prompted many questions and stimulated further research in this area. Serum glycated albumin (GA) is now under investigation and researchers have hypothesized it to be an alternative marker for glycemic control in patients with diabetes, including those with ESRD.5,8

   Unlike HbA1c, which provides an integrated measure of plasma glucose over the past 120 days, mirroring the life span of an erythrocyte, GA is a glycemic indicator of the immediately previous two weeks. Glycated albumin is not affected by changes in the survival time of erythrocytes or changes in albumin concentration.5 Additionally, GA is not influenced by erythropoietin therapy.8 This is measured enzymatically via a liquid chemistry system and calculated as the percentage of GA relative to total serum albumin.4,5 This percentage is reportedly an accurate reflection of glycemic control. Therefore, one should consider the percentage of GA a more useful marker than HbA1c for determining glycemic control in patients with diabetes on hemodialysis.4

   A study by Inaba and co-workers reported a significantly lower value of HbA1c relative to plasma glucose and GA in hemodialysis patients with diabetes in comparison to patients with diabetes and without chronic renal failure (CRF).5 This study suggests that the measurement of HbA1c would result in underestimation of glycemic control in hemodialysis patients with diabetes.

   The authors further explained the mechanism for the significantly lower HbA1c value being due to anemia and/or erythropoietin injections in their patient population. An analysis validated that the erythropoietin use, rather than hemoglobin reduction, was an independent factor significantly associated with the HbA1c value. This study found significantly lower HbA1c values in hemodialysis patients who had diabetes and underwent treatment with erythropoietin in comparison to those on hemodialysis without diabetes. Furthermore, the plasma glucose and GA were not significantly different between the study groups.5

   Fukuoka and colleagues performed a prospective follow-up study, which showed a significant association between hyperglycemia and poor survival. This association was reflected by higher GA levels but not by HbA1c levels.8

   Glycated albumin is not only a significant indicator of hyperglycemia but also acquires biologic properties linked to the pathogenesis of diabetic vascular complications. This allows GA to aid in predicting the development of vascular complications in hemodialysis patients with diabetes.5

   Yamada and co-workers found a significant association with the presence of peripheral vascular calcification in hemodialysis duration and GA.11 When researchers replaced GA with HbA1c in the same model, the association was not significant. It is their work which suggests that glycated albumin might be a better indicator of glycemic control than HbA1c, and raises the possibility that improving glycemic control might aid in the prevention against the development of peripheral vascular calcification in patients with diabetes who are on hemodialysis.

   As with HbA1c, glycated albumin is not the best evaluation of glycemic control in all populations. One must take care in using the percentage of GA as the best prognostic indicator for glycemic control in special populations with abnormal turnover of serum albumin. These patients would include those with heavy proteinuria, liver cirrhosis, thyroid disease, inflammatory diseases or those on peritoneal dialysis.4,5

In Conclusion

   Although HbA1c holds the promise of more efficient patient care and improved management of diabetes, it is not a reliable form of assessing glycemic control in patients on hemodialysis.5,8,10 Furthermore, one should not use HbA1c as a diagnostic indicator of diabetic management in those on hemodialysis.

   Recent studies argue that GA is the way toward the future evaluation of glycemic control with its more reliable reflection of blood glucose control in patients with diabetes and end-stage renal disease in comparison to HbA1c.8,9 Future investigations are needed as the search continues for a reliable method of evaluating glycemic control in both patients with diabetes and diabetics requiring hemodialysis.

Dr. Adams is a third-year podiatry resident within the INOVA Fairfax Podiatric Residency Program in Falls Church, Va.

Dr. Steinberg is an Assistant Professor in the Department of Plastic Surgery at the Georgetown University School of Medicine in Washington, D.C. Dr. Steinberg is a Fellow of the American College of Foot and Ankle Surgeons.

References:

1. American Diabetes Association (www.diabetes/org/diabetes-statistics.jsp). 2. Brownlee M, Hirsh IB. Glycemic variability: a hemoglobin A1c- independent risk factor for diabetic complications. JAMA 2006; 295(14): 1707-1708. 3. Kalantar-Zade, Kopple JD, Regidor DL, et al. A1C and survival in maintenance hemodialysis patients. Diabetes Care 2007; 30(5):1049-1055. 4. Uzu T, Hatta T, Deji N, et al. Target for glycemic control in type 2 diabetic patients on hemodialysis: effects of anemia and erythropoietin injection on hemoglobin A1c. Therapeutic Apheresis and Dialysis 2009; 13(2):89-94. 5. Inaba M, Okuno S, Kumeda Y, et al. Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J Am Soc Nephrol 2007; 18:896-903. 6. Mitka M. Hemoglobin A1c poised to become preferred test for diagnosing diabetes. JAMA 2009; 310(15):1528. 7. Schwartz KL, Monsur JC, Bartoces MG, et al. Correlation of same-visit HbA1c test with laboratory-based measurements: A MetroNet Study. BMC Family Practice 2005; 13(6):28. 8. Fukuoka K, Nakaao K, Morimoto H, et al. Glycated albumin levels predict long-term survival in diabetic patients undergoing haemodialysis. Nephrology 2008; 13(4):278-283. 9. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 32(7):1327-34, 2009. 10. Chujo K, Shima K, Tada H, et al. Indicators for blood glucose control in diabetics with end-stage chronic renal disease: GHb vs. glycated albumin. J Med Invest 2006; 53(3-4):223-8. 11. Yamada S, Inaba M, Shidara K, et al. Association of glycated albumin, but not glycated hemoglobin, with peripheral vascular calcification in hemodialysis patients with type 2 diabetes. Life Sci 2008; 83(13-14):516-9.