The clinical usefulness of glycated albumin in patients with diabetes and chronic kidney disease: Progress and challenges
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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2022, Clinica Chimica ActaCitation Excerpt :Indeed, the utility of glycated hemoglobin in patients with chronic kidney disease may be problematic because of the reduction of red cell life and treatment with erythropoietin [59,60]. However, GA is known to be a precursor of advanced glycation end products (AGEs), and may be correlated with adverse outcomes in patients under dialysis [61]. Very recent findings seem to indicate that GA is able to predict all-cause mortality in diabetic patients under dialysis [62] but the glycated form of albumin seems to be cleared at a faster rate respect to the non-glycated form, and these points need further investigations [63,64].
Glycated albumin as biomarker: Evidence and its outcomes
2021, Journal of Diabetes and its ComplicationsCitation Excerpt :The following two important results from meta-analysis have also been reported: first, GA is reported to be a good prognostic marker in patients with CKD. The pooled hazard ratio (HR) of the meta-analysis, which included six articles with a total of 1102 patients with CKD, was 1.05 (P < 0.001), showing that elevated concentrations of GA were consistently associated with an increased risk of mortality43; s, another study included 25,932 dialysis patients across 12 studies with maximum follow-up of 11 years, concluded that GA predicts all-cause mortality risk in dialysis patients with diabetes.44 The Japanese guide, “Best Practice for Diabetic Patients on Hemodialysis 2012” states that the A1C level might be used only as a reference, and tentative targets for glycemic control were set as casual plasma glucose levels (or 2-h postprandial plasma glucose levels) less than 180–200 mg/dL for pre-dialysis patients and GA levels less than 20.0%.
Hypoglycemic and hypolipidemic effects of total glycosides of Cistanche tubulosa in diet/streptozotocin-induced diabetic rats
2021, Journal of EthnopharmacologyCitation Excerpt :Diabetes is a progressive and chronic metabolic disorder which is mainly characterized by hyperglycemia. At present, FPG is a specific measure of blood glucose concentration, OGTT is a sensitive detection criterion of early abnormalities in glucose disposal, while HbA1c is widely used as a gold standard index for glycemic control reflects average glucose level over 120 days preceding the test (Nagy et al., 2018; Gan et al., 2018). FPG, OGTT and HbA1c are used clinically for the diagnosis and management of prediabetes and diabetes (Chai et al., 2017).
Nutritional and metabolic management of the diabetic patient with chronic kidney disease and chronic renal failure
2021, Nutritional Management of Renal Disease, Fourth EditionHemodialysis Centers Guide 2020
2021, NefrologiaCitation Excerpt :Glycated albumin is also an early precursor of advanced glycation end-products (AGE), which cause alterations of different cell proteins and organelles. It seems reasonable to determine glycosylated hemoglobin or preferably GA in diabetic patients at least twice a year318–320. Troponin, at high concentrations, is associated to a poorer long-term cardiovascular prognosis in patients with severe renal failure.
Review of methods for detecting glycemic disorders
2020, Diabetes Research and Clinical PracticeCitation Excerpt :As GA is not affected by the same limitations as hemoglobin, it may be an acceptable alternative biomarker of glycemic control when HbA1c is unreliable as in CKD, particularly during hemodialysis [300]. It also seems to be a better predictor of cardiovascular complications and risk of hospitalization or death in these patients when HbA1c is especially unreliable in the presence of anemia or erythropoietin administration [301,302]. Similar to fructosamine, the use of GA is limited in pathological conditions affecting albumin metabolism including nephrotic syndrome, hyperthyroidism, glucocorticoid or iron therapy, malnutrition, and advanced liver disease [280,303–305].
Disclosure: All the authors declared no competing interests.