The clinical usefulness of glycated albumin in patients with diabetes and chronic kidney disease: Progress and challenges

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Abstract

Prolonged hyperglycemia leads to a non-enzymatic glycation of proteins, and produces Amadori products, such as glycated albumin (GA) and glycated hemoglobin (HbA1c). The utility of HbA1c in the setting of chronic kidney disease (CKD) may be problematic since altered lifespan of red blood cells, use of iron and/or erythropoietin therapy, uremia and so on. Therefore, as an alternative marker, GA has been suggested as a more reliable and sensitive glycemic index in patients with CKD. In addition to the mean plasma glucose concentration, GA also reflects postprandial plasma glucose and glycemic excursion. Besides, with a half-life of approximately 2–3 weeks, GA may reflect the status of blood glucose more rapidly than HbA1c. GA is also an early precursor of advanced glycation end products (AGEs), which cause alterations in various cellular proteins and organelles. Thus, high GA levels may correlate with adverse outcomes of patients with CKD. In this review, the clinical usefulness of GA was discussed, including a comparison of GA with HbA1c, the utility and limitations of GA as a glycemic index, its potential role in pathogenesis of diabetic nephropathy and the correlations between GA levels and outcomes, specifically in patients with diabetes and CKD.

Introduction

Chronic kidney disease (CKD) is a growing global health problem and diabetes mellitus (DM) is the leading cause of CKD. One study found that patients with diabetes (type 1 or 2) were 7 times more likely to have clinically substantial CKD than those without diabetes.1 Diabetes has become the primary cause of new cases of end-stage renal disease (ESRD).2 In the meantime, the decline in renal function impairs the clearance and metabolism of renal glucose and insulin. Besides, renal failure causes related changes in insulin signaling, glucose transport and metabolism. All of these factors also make diabetes more prevalent in the CKD patients.

Good glycemic control is associated with a better clinical outcome of patients with diabetes and chronic kidney disease.3., 4., 5. At present, we often use fasting plasma glucose (FPG), 2 h postprandial plasma glucose (2 h PG) and random plasma glucose to measure the actual glucose levels. However, these indices often affected by short-term lifestyle changes, and show significantly variability within individuals. So glycated proteins are frequently used to provide an index of glycemic control over a period of time. Hemoglobin A1c (HbA1c), which reflects average glucose levels (AG) over the 120 days preceding the test, is widely used as a gold standard index for glycemic control in clinical practice. However, the utility of HbA1c in the setting of CKD has been questioned since CKD is accompanied by several factors such as anemia, altered erythrocyte turn-over and erythropoietin treatment.6., 7., 8. Therefore, serum glycated albumin (GA), as an alternative marker, has been suggested as a more reliable and sensitive glycemic index than HbA1c in diabetic patients with CKD,9., 10., 11., 12. since it is not influenced by anemia and associated treatments. Fructosamine is a generic term that refers to all glycated serum proteins including GA in blood serum and GA measures specifically the glycation product of albumin. The clinical assays for glycated albumin typically express their results in terms of the ratio of the amount of glycated albumin versus the total amount of albumin that is present. This feature means that these methods are not generally affected by changes in the overall concentration of albumin.13,14

Recently, some studies have found that GA was a good predictor of adverse outcomes of diabetic patients with CKD,15., 16., 17., 18., 19., 20., 21., 22., 23. and this may because GA is involved in many pathologic processes. GA is the major form of circulating Amadori-type glycated proteins and it is an early precursor of advanced glycation end products (AGEs),24 which bind to AGE receptors (RAGEs) opening the floodgate of deleterious downstream signals including increased reactive oxygen species (ROS) production, inflammatory cell activation, inappropriate increase of angiotensin II (Ang II), and release of growth factors.25,26 For example, some latest studies showed the potential role of GA in pathogenesis and predicting diabetic nephropathy (DN) in patients with DM.27 Then by observing the degree of increase in GA, measures can be taken to prevent DN before evolving structural damage is clinically apparent.

This review summarizes current knowledge about the clinical usefulness of glycated albumin in patients with diabetes and CKD and we will mainly discuss: (1) Albumin: biochemical and glycation aspects; (2) GA as a marker for glycemic control; (3) GA may function as a pathogenic protein and predictor of DN in diabetes; and (4) GA as a prognosis indicator in patients with CKD.

Section snippets

Albumin: biochemical and glycation aspects

Albumin is the most abundant circulating protein, accounting for 50–60% of total plasma proteins. It comprises a single polypeptide chain of 585 amino acids with abundance of lysine (59) and arginine (24) residues and contains 35 cysteine residues, 34 of which form 17 disulfide bridges, important for the overall tertiary structure of the protein.28., 29., 30., 31. One of the main processes affecting the structure of albumin is glycation, a nonenzymatic chemical reaction between reducing sugars

Average glucose level

Both HbA1c and GA are spontaneously glycated over their circulating lifespan, and thus are the biomarkers for time-averaged blood glucose concentrations. But the shorter half-life makes GA a much more dynamic marker for glycemic control that can be used to assess the efficacy of diabetes medication therapy and short-term changes in glycemic control. In the setting of CKD, many studies considered GA may more accurately in reflecting the recent average glucose level.7,54., 55., 56., 57., 58., 59.

GA may function as a pathogenic protein and predictor of DN

The nonenzymatic glycation reaction occurs between high levels of glucose and reactive amino acid groups followed by the formation of Schiff bases, Amadori products, and finally AGEs in a stepwise manner.29,114 AGEs are prevalent in patients with CKD because of a failure in detoxification of glycation intermediates by the kidney. GA, an early Amadori-type glycation protein, it is viewed as an early precursor of AGE.24 In the glycated form, albumin does not simply present changes in its

GA as a prognosis indicator in patients with CKD

Recently, many studies have reported that elevated glycated albumin levels were associated with adverse outcomes of patients with CKD, independent of rigorously measured potential confounding variables (Table 5).15., 16., 17., 18., 19., 20., 21., 22., 23. However, these studies are observational studies and the associations have not been verified by the large-scale clinical trials. Therefore, we performed a meta-analysis to identify whether high level of GA was a significant predictor of

Conclusions

In patients with diabetes and CKD, GA could be a better glycemic index than HbA1c because it is not affected by the lifespan of red blood cells, use of iron and/or erythropoietin therapy, uremia and so on. Addition to an indicator of the mean plasma glucose concentration, GA also reflects postprandial plasma glucose and glycemic excursion which are closely associated with diabetic complications such as cardiovascular disease. Besides, the shorter half-life makes GA a much more dynamic marker

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. H0517/81560132), the Supporting Project for the Foregoers of Main Disciplines of Jiangxi Province (No. 20162BCB22023), and the “5511” Innovative Drivers for Talent Teams of Jiangxi Province (No. 20165BCB18018).

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    Disclosure: All the authors declared no competing interests.

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