Clinica Chimica Acta 413 (2012) 1555–1561

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Clinica Chimica Acta

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Invited critical review

Glycated albumin in diabetic patients with chronic kidney disease

Cai-Mei Zheng a, 1, Wen-Ya Ma b, 1, Chia-Chao Wu c, Kuo-Cheng Lu b,⁎
a
Division of Nephrology, Department of Medicine, Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan
b
Department of Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
c
Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Chronic hyperglycemia results in a non-enzymatic glycation of proteins, and produces Amadori products,
Received 11 March 2012 such as glycated albumin (GA), glycosylated hemoglobin (HbA1c), and fructosamine. In current clinical
Received in revised form 23 April 2012 practice, long-term glycemic control is assessed by quarterly measurements of HbA1c. Since the degree
Accepted 23 April 2012
of hemoglobin glycosylation depends not only on the level of glycemic control, but also on the lifespan
Available online 10 May 2012
of red blood cells, patients with hemoglobin disorders or anemia of any cause may have erroneous
Keywords:
HbA1c levels, and consequently receive insufficient treatment. Patients with chronic kidney disease
Amadori reaction (CKD) often suffer from various types of anemia, and consequently, they are frequently treated with iron
Chronic kidney disease and/or erythropoietin therapy or frequent blood transfusion. Thus, serum GA is a potentially useful glyce-
Diabetes mic index in diabetic patients with CKD, since it is not influenced by anemia and associated treatments. GA
Glycated albumin may also reflect the status of blood glucose more rapidly (2–3 weeks) than HbA1c (2–3 months), and is
Glycated hemoglobin beneficial in those with wide variations in blood glucose or at higher risk for hypoglycemia. If clinical
investigations support its utility, it may be applicable as a screening tool for all patients with diabetes
during routine health examinations. Serum GA levels are also associated with AGE-related fluorescence
and the number of glycation sites, and it may influence the structural and functional changes inalbumin.
Since end-stage renal disease is an extreme microvascular complication of diabetic nephropathy, CKD
patients with diabetes should be carefully managed to prevent disease progression. In this review, the clin-
ical aspects of GA were discussed, including a comparison of GA with other glycated proteins, the utility
and limitations of GA as a glycemic index, its influence on the therapeutic effects of hypoglycemic agents,
its correlations with vascular complications, and its potential role in pathogenesis, specifically in diabetic
patients with CKD.
© 2012 Elsevier B.V. All rights reserved.

Contents

1. Amadori reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1556

2. Structural and glycation site changes of albumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1556
2.1. Binding site changes with protein glycation: effects on drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557
2.2. Measurement of glycated albumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557
3. Clinical significance of glycated proteins in diabetic patients with chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . 1557
3.1. Glycemic control and prognosis in diabetic patients with CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557
3.2. Glycated albumin as a marker of glycemic control and comparison of other glycemic indices . . . . . . . . . . . . . . . . . . . . 1557
3.2.1. Glycated hemoglobin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557
3.2.2. Fructosamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1558
3.2.3. Glycated albumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1558
3.2.4. Conversion between GA and HbA1c values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1558
3.3. Diabetic patients on dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1558
4. Other clinical conditions in diabetic patients with CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559
4.1. Screening and diagnosis of diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559

⁎ Corresponding author at: Division of Nephrology, Department of Medicine, Cardinal Tien Hospital, School of Medicine, Fu-Jen Catholic University, 362, Chung-Cheng Rd,
Hsin-Tien, New Taipei City, Taiwan. Tel.: + 886 2 29155739; fax: + 886 2 29107920.
E-mail address: kuochenglu@gmail.com (K-C. Lu).
1
These authors contributed equally to this work.

0009-8981/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.cca.2012.04.025
1556 C-M. Zheng et al. / Clinica Chimica Acta 413 (2012) 1555–1561

4.2. Bone metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559

4.3. Diabetic nephropathy and contrast-induced acute kidney injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559

1. Amadori reaction four steps [2]: (1) non-enzymatic condensation of α- hydroxy-aldehydes

Chronic hyperglycemia is responsible for non-enzymatic glycation
of proteins resulting from the covalent binding of glucose to amino
acids [1]. Endogenous glycation primarily occurs in the bloodstream,
and involves a small proportion of the absorbed glucose. Glycation
is the first step in the production of these molecules and involves a
complex series of very slow reactions in the body, known as Amadori
reactions, Schiff base reactions, and Maillard reactions, which ulti-
mately lead to the formation of advanced glycation end-products
(AGEs; Fig. 1A) [1]. The Amadori reaction (Fig. 1B) [2], a non-
enzymatic pathway that links the reduction of carbohydrates with
reactiveamino groups, leads to the formation of Amadori products
and AGEs. A series of complex reactions occur after the initial
carbonyl-amine reaction. These reactions generally follow the following
with a suitable free amine group of proteins or nucleic acids to form a
glycosylamine (reversible step); (2) rearrangement of the glycosylamine
to ketosamine, also known as the Amadori-rearrangement product
(ARP) [3]; (3) degradation and dehydration of ARP into amino or carbo-
nyl intermediates; and (4) the reaction of carbonyl intermediates with
other amino groups and subsequent rearrangements to form AGEs.
2. Structural and glycation site changes of albumin
Glycation of albumin impacts its normal physiological functions,
such as the binding affinity of drugs and hormones, esterase-like activ-
ity, and antioxidant effects. The Tritium label has been used to identify
the glycation sites of albumin, and the principle glycation site in albu-
min has been located at Lys-525 in normal individuals. Garlick et al.

Fig. 1. A) Early and advanced glycation in hyperglycemia. The formation of an advanced glycation end-product (AGE) involves the initial formation of a Schiff base, then an Amadori
rearrangement product (ARP), and finally an AGE. The first two steps in this reaction are reversible, whereas the last step is irreversible. R-NH2: free amine group of proteins or
nucleic acids. B) Initially, glycation involves covalent reactions between the free amino groups of amino acids (e.g. lysine, arginine, or protein terminal amino acids) and sugars
(e.g. glucose, fructose, ribose, etc.) to create a Schiff base (glycosylamine), and then the production of Amadori rearrangement products (ARP), such as hemoglobin A1C
(HbA1c), glycated albumin (GA), and fructosamine. An attack by the O-6 on the carbonyl group of open chain glycosylamine will close the ring, producing a 1-deoxy-1-amino-
D-glycopyranose compound (α,β-glycopyranosylamine).
 C-M. Zheng et al. / Clinica Chimica Acta 413 (2012) 1555–1561
demonstrated that Lys-525 accounts for 48% of all glycated albumin
(GA) in normal individuals [4], while Iberg et al. reported that the prin-
cipal glycation site, Lys-525, is responsible for 33% of all GA in patients
with unstable blood glucose levels [5]. Using liquid chromatography/
mass spectrometry, Kisugi et al. followed patients with marked hyper-
glycemia and GA values up to 94.1%, and found additional glycation
sites during times of poor glycemic control [6]. Furthermore, GA values
declined rapidly after treatment, as did the number of glycation sites
and AGE-related fluorescence. Thus, changes in the number and ratio
of the major binding sites in response to various degrees of hyperglyce-
mia may reflect structural or even functional changes in albumin fol-
lowing glycation.
2.1. Binding site changes with protein glycation: effects on drug
interactions
Protein modifications alter their biological functions, including drug
interactions. Therefore, glycation may affect the binding of medications
to protein in patients with diabetes. It is clinically important to deter-
mine how glycation affects normal protein binding of oral hypoglycemic
agents (OHA) during hyperglycemia, as it may impact on their therapeu-
tic effects. The binding affinities of OHA to glycated human serum albu-
min were found to be lower than those of albumin. The order of
binding affinities of OHA from highest to lowest were as follows:
glibenclamide, acetohexamide, tolbutamide, gliclazide, and metformin
[7]. Additionally, it was found that even a small increase in the free
(non-protein bound) fraction of OHA may lead to severe hypoglycemia
[7]. Albumin, a major binding protein (66.5 kD), has two major binding
sites for drugs: Sudlow sites I and II [8]. Sudlow site I is located on sub-
domain IIA of albumin and binds to a variety of drugs, including warfarin,
azapropazone, phenylbutazone, and salicylate [9]. Sudlow site II is locat-
ed on subdomain IIIA of albumin and binds to ibuprofen, fenoprofen,
ketoprofen, benzodiazepines, and L-tryptophan [9]. Both Sudlow sites I
and II bind to first-generation sulfonylureas, such as acetohexamide
and tolbutamide [10,11]. In a recent study, the binding of gliclazide, a
second generation sulfonylurea, to human serum albumin (HSA) at var-
ious stages of glycation was determined via a bio-interaction analysis
with high-performance affinity chromatography (HPAC) [12]. While
some glycated HSA samples revealed similar affinities to normal HSA at
Sudlow site I, all glycated HSA samples differed in their affinities at
Sudlow site II compared with normal HSA [12]. Thus, the glycation mod-
ification can have distinct effects on the interactions between medication
and albumin at various binding sites.
2.2. Measurement of glycated albumin
Measuring GA may provide useful information on glycemic con-
trol when monitoring the effects of changes in therapy. Affinity chro-
matography [13], ion exchange chromatography [14], and high
performance liquid chromatography (HPLC) [15] can be used to mea-
sure GA levels as a ratio of GA peak area to total albumin peak area,
and these techniques are specific for measuring glycated albumin.
However, thiobarbituric acid (TBA) [16] and enzymatic assays [17]
can be used to determine GA levels as a ratio of total glycated
amino acid concentration to albumin concentration, and these tech-
niques are specific for measuring glycated amino acids in albumin.
In regards to various immunoassays [18] and the enzyme-linked
boronate affinity-immunoassay [19], GA levels are measured as a ratio
of glycated amino acid concentration to albumin concentration. Howev-
er, GA levels may differ depending on the specificity of the antibody
used. Furthermore, the steric hindrance of the antibody or enzyme-
linked boronate should also be taken into consideration. Thus, the de-
termination of GA levels via these methods may be affected. Despite
this, enzymatic methods are particularly suitable for measuring GA, as
the Committee on Diabetes Mellitus Indices and Japanese Society of
1557
Clinical Chemistry (JSCC) stated the importance of measuring all
glycation sites [20].
The general performance of enzymatic assays for GA is good, and
samples appear to be stable for 4 years at −80 °C. In the Diabetes Con-
trol and Complications Trial (DCCT), Nathan and colleagues [21] studied
the stability of samples and concluded that “samples stored for as long
as 23 years are suitable for the GA assay.” The reference range of the en-
zymatic method in the American population was determined to be
11.9–15.8%. Tominaga and colleagues [22] reported that the reference
range of GA in the Japanese population was 12.3–16.9%, as published
in a report by the Committee on Standardization of Laboratory Testing
related to Diabetes Mellitus of the Japan Diabetes Society.
3. Clinical significance of glycated proteins in diabetic patients
with chronic kidney disease
3.1. Glycemic control and prognosis in diabetic patients with CKD
Diabetes mellitus is not only a leading cause of chronic kidney disease
(CKD), but is also an important comorbidity in established CKD. Glycemic
control may decrease the incidence of new-onset microalbuminuria [23],
delay the progression of diabetic nephropathy [24], limit end-organ
damage, and reduce cardiovascular morbidity and mortality in uremic
patients on hemodialysis (HD) [25].
Compared to the general population, glycemic control in patients
with CKD is complicated by alterations in glucose and insulin homeo-
stasis. Uremic toxins suppress hepatic gluconeogenesis and regulate
peripheral glucose utilization. Additionally, insulin resistance may
not lead to a compensatory increase in insulin secretion, as compared
to those without kidney diseases, due to concomitant metabolic aci-
dosis, 1,25-dihydroxyvitamin D deficiency, and secondary hyperpara-
thyroidism [26]. Periodic improvements in uremia, acidosis, and
phosphate handling may also alter insulin secretion.
In the early stages of CKD, almost all hypoglycemic agents can be
prescribed. However, in patients with moderate to advanced CKD,
some medications are contraindicated and others must be used with
caution at a reduced dose [27]. Consequently, insulin is recommended
in this population with a careful dose titration strategy. Furthermore,
a prolonged duration of insulin action is frequently seen in CKD pa-
tients due to the progressive decrease in renal metabolism and clear-
ance [28]. Due to the associated malnutrition and impaired renal
gluconeogenesis, patients with CKD carry a higher risk of hypoglyce-
mia [29]. Furthermore, HD may increase insulin and glucose clearance
[30], whereas peritoneal dialysis (PD) may affect the glycemic status
due to its high-glucose concentrate dialysate solutions [31]. There-
fore, maintaining a stable glycemic status in uremic patients with di-
abetes has been a significant clinical challenge. In the CKD population,
the recommended targets of therapy are to achieving a glycated he-
moglobin A1c (HbA1c) value between 6 and 7%, a fasting plasma
glucose concentration b140 mg/dL, and a postprandial glucose con-
centration b200 mg/dL [27]. However, a reliable glycemic index is re-
quired to achieve optimal glycemic control and minimize the risk of
hypoglycemia in patients with CKD.
3.2. Glycated albumin as a marker of glycemic control and comparison of
other glycemic indices
GA, fructosamine, and more commonly, HbA1c, are non-
enzymatically glycated proteins that are utilized to monitor glycemic
status in patients with diabetes [32,33]. However, special consider-
ations should be taken into account when applying and interpreting
these indices in patients with CKD.
3.2.1. Glycated hemoglobin
HbA1c is produced by the non-enzymatic reaction of a free primary
amine (terminal valine residue) on the beta-chain of the hemoglobin
1558 C-M. Zheng et al. / Clinica Chimica Acta 413 (2012) 1555–1561
molecule with the carbonyl group of glucose [31]. HbA1c is widely used
as a marker of glycemic control and is highly prognostic for long term
diabetes-related complications in the general diabetic population
[34]. With improvements and standardization of HbA1c assays [35],
these assays were recently recommended for the diagnosis of diabetes
[36]. Since the average life span of erythrocytes in blood is approxi-
mately 120 days, HbA1c reflects the peripheral blood glucose concen-
tration over a period of 2–3 months. However, since the most recent
glycemic status has a great impact on HbA1c levels, HbA1c is not sim-
ply the “average” of the glucose concentrations during this period [37].
Thus, HbA1C does not represent the true glycemic status of patients
with wide fluctuations of glucose concentrations.
HbA1c values are influenced by a variety of factors that alter the
survival of red cells, such as iron deficiency anemia [38,39], hemolytic
anemia [40,41], CKD-related anemia [42], and various hemoglobinopa-
thies [43]. Thus, in these conditions, HbA1c levels should be interpreted
with caution.
In diabetic patients with end-stage renal disease (ESRD), HbA1c
levels appear not to be an appropriate marker of glycemic status. Mea-
surements of HbA1c underestimate and inaccurately reflect the long-
term glycemic conditions of advanced CKD and dialysis-dependent pa-
tients [44]. Several features, including the lifespan of red blood cells (i.e.
a reduction of 20–50% of normal) [45,46], use of iron and/or recombi-
nant human erythropoietin therapy, uremia, and the need for frequent
blood transfusions [46], all contribute to this discrepancy. Iron and/or
erythropoietin treatment may be followed by an immediate fall in
HbA1C levels without significant changes in glycemic status [47–49],
which is likely due to the stimulation of erythropoiesis with an in-
creased ratio of young to old erythrocytes, and thus a reduction in the
proportion of glycated hemoglobin [50]. Moreover, an acquired form
of hemoglobin, carbamylated hemoglobin, which is formed under ure-
mic conditions, may interfere with some HbA1c assays, and result in
an overestimation of HbA1c values [51,52].
3.2.2. Fructosamine
Fructosamine is an alternative glycemic index that has a shorter
half-life than HbA1c, and thus, reflects recent (i.e. 1–3 weeks) glycemic
status. It primarily originates from the non-enzymatic glycation of al-
bumin (~90%), as well as other proteins [53]. Fructosamine is a generic
term that refers to all glycated serum proteins, including GA, in blood
serum. Measurements of serum fructosamine concentrations are rou-
tinely corrected for albumin or total protein values; however, this cor-
rection remains controversial [54]. Although fructosamine is not
altered by disorders of hemoglobin metabolism, it is affected by disor-
ders in protein turnover, such as dysproteinemias [3]. Moreover, the
presence of low molecular weight substances (i.e. urea and uric acid)
may also impact on fructosamine concentrations [55]. Lamb et al. [56]
reported that serum fructosamine concentrations were elevated in
HD patients. Moreover, the corrected fructosamine value is reportedly
more reliable than HbA1c for glycemic status in uremic patients on ei-
ther HD or PD [33,56,57]. Albumin-corrected fructosamine levels were
reported to correlate better than HbA1c with hospitalization and infec-
tion in diabetic patients on HD [33]. Whether this observation is due to
fructosamine per se or a low albumin concentration in patients suscep-
tible to infection remains uncertain. Lastly, elevated fructosamine
levels were found to predict cardiovascular mortality in non-uremic
patients without diabetes [58], but the prognostic role of fructosamine
in HD patients is unknown.
3.2.3. Glycated albumin
GA is a ketoamine formed from a non-enzymatic oxidation of al-
bumin by glucose. Evidences suggests that GA as a better glycemic in-
dicator than HbA1c in diabetic dialysis patients [59]. Similar to
fructosamine, GA reflects the glycemic status over the preceding
2–3 weeks. Additionally, GA is not influenced by albumin concentra-
tions, as the calculated GA value is a ratio of GA concentration to
total serum albumin [4]. Although serum GA values are primarily
influenced by glucose, it is also influenced by altered serum albumin
metabolism [54,60,61]. Thus, increased GA values may be found in
those with prolonged half-lives of albumin, such as patients with
hepatic cirrhosis [62] or hypothyroidism [61]. Conversely, excess thy-
roid hormones promote albumin catabolism and result in significant-
ly low GA values in patients with thyrotoxicosis [61]. Proteinuria may
also decrease GA values in CKD patients with diabetes, particularly in
the nephrotic range [63]. Therefore, in patients with diabetic ne-
phropathy (stage III or IV) and overt proteinuria, GA values may be
lower relative to plasma glucose levels as a result of an increased
turnover in albumin metabolism.
GA has been found to correlate better with glycemic status than
HbA1c in patient with advanced CKD [48,59,64], since it is not
influenced by the lifespan of red blood cells or erythropoietin treat-
ment. The rapid changes in GA values in response to glucose concen-
trations are beneficial in diabetic patients with fluctuating glucose
levels, such as those with postprandial hyperglycemia, great glucose
variability, or abrupt changes in glycemic status over a very short pe-
riod of time [32,65,66]. Thus, GA may be a more useful marker of gly-
cemic index than HbA1c, especially in patients with conditions, such
as variant hemoglobinopathies, iron deficiency anemia [38], and
pregnancy [39].
In addition to reflecting blood glucose values, GA is also a surro-
gate marker for vascular complications. GA is associated with vascular
calcification in diabetic patients on dialysis [67]. Increased GA levels
may also be associated with diminished immune function [68], in-
creased oxidative stress [69], disturbed cholesterol homeostasis
[70], impaired endothelial function [71], and proinflammatory re-
sponses [72], suggesting that GA may play a role in the pathogenesis
of atherosclerosis. Indeed, a significant relationship between elevated
serum GA and coronary artery stenosis has been previously reported
[73,74].
3.2.4. Conversion between GA and HbA1c values
With improvements in the GA assay and advantages over HbA1c
under specific conditions, GA is becoming increasingly used in diabet-
ic clinics [65]. Although HbA1c and serum GA proportionally change
with plasma glucose concentrations and with each other, discrepan-
cies between these values are still an issue for clinical application.
Tahara et al. analyzed the conversion between HbA1c and GA values,
and found that a 1% increase in HbA1c corresponds to a 4% increase in
GA [75]. The linear regression equation used to determine this con-
version was as follows: HbA1c = 1.73 + 0.245 GA. It is important to
standardize the conversion factor for GA values to corresponding
HbA1c values or plasma glucose concentrations to widely apply GA
as a glycemic index for diabetic patients in the future.
3.3. Diabetic patients on dialysis
As discussed earlier, in diabetic patients on either HD or PD, HbA1c
values are falsely lower compared to patients without nephropathy
[48,59,64]. This underestimation in the true glycemic status may re-
sult in an inadequate treatment of hyperglycemia. Conversely, car-
bamylated hemoglobin in the uremic condition may result in an
overestimation of glycemic status [51,52], thereby increasing the po-
tential risk of hypoglycemia. These factors make HbA1c even more
unreliable as a glycemic index in patients on dialysis. Recent studies
recommend the use of GA rather than HbA1c for monitoring glycemic
control in patients on dialysis [48,59,64]. However, albumin homeo-
stasis may be abnormal in these patients, and there is insufficient
data for the reference range in different populations regarding race,
severity of CKD, mode of dialysis, and other factors. Thus, currently
available data are insufficient to conclude whether GA can replace
HbA1c for the assessment of glycemic status in diabetic patients
with ESRD.
 C-M. Zheng et al. / Clinica Chimica Acta 413 (2012) 1555–1561
The role of GA and HbA1c in predicting the outcome of diabetic di-
alysis patients is of great interest. Okada et al. compared these glyce-
mic indices in predicting cardiovascular complications and survival in
78 diabetic patients on dialysis [76]. Neither GA nor HbA1c predicted
mortality, but higher GA values were associated with the develop-
ment of cardiovascular disease [76]. In another Japanese population
of 98 uremic diabetic patients, Fukuoka et al. found that higher GA
values at initiation of hemodialysis predicted mortality and cardio-
vascular morbidity, whereas HbA1c did not predict survival [77]. Sim-
ilarly, William et al. evaluated the role of HbA1c in glycemic control in
diabetic uremic patients, and found that there were no significant
correlations between HbA1c and 12-month survival in a large nation-
al ESRD database [78]. Recently, Freedman and colleagues investigat-
ed the prognostic value of GA in a cohort of 444 diabetic dialysis
patients [79]. GA, but not HbA1c, significantly predicted the risk of
death and hospitalization. It was also determined that every 5% in-
crease in GA value was associated with a 14% higher risk for all-
cause mortality [79]. However, in a very large scale study on 23,618
diabetic dialysis patients, high HbA1c values were associated with in-
creased all-cause and cardiovascular death after adjusting for poten-
tial confounders, especially in those without significant anemia
(hemoglobin >11.0 g/dl) [80]. Taken together, GA appear to be a bet-
ter prognostic predictor of survival and risk of cardiovascular events
in diabetic dialysis patients than unadjusted HbA1c. However, until
a standardized assay and a proper therapeutic target are available,
HbA1c, albeit with careful interpretation, remains a reasonable mea-
sure of glycemic control and a prognostic predictor in this population.
The potential roles of GA in diabetic patients with CKD in clinical
practice were summarized in Table 1.
4. Other clinical conditions in diabetic patients with CKD
4.1. Screening and diagnosis of diabetes
A community-based population study carried out in Japan indicat-
ed that GA was useful for diabetes screening in the general popula-
tion, with a cutoff of >15.5% indicating early phase diabetes [20]. In
a Chinese population, Li and colleagues used both HbA1c and GA to
improve the efficacy of diabetic screening [81]. Those with HbA1c
≥6.1% or serum GA ≥17.1% were recommended to undergo an oral
glucose tolerance test (OGTT) to confirm the diagnosis of diabetes
[81]. It is known whether uremic patients on dialysis have a greater
Table 1
The roles of glycated albumin in diabetic patients with chronic kidney disease.
Clinical significance
As a glycemic index in diabetic Could be better than HbA1c in those:
patients with CKD With anemia
Undergoing erythropoietin treatment
Undergoing hemodialysis
With large fluctuations in glucose levels
Limited use in those with:
Liver cirrhosis
Nephrotic-range proteinuria
Inadequate evidence:
Early stages of CKD
Patients on peritoneal dialysis
As a prognostic factor in diabetic Could be better than HbA1c in:
patients with CKD Predicting survival in dialysis patients
Could be involve in pathogenesis of:
Cardiovascular complications
Diabetic nephropathy
Contrast-induced acute kidney injury
Inadequate evidence:
Early and moderate stages of CKD or non-
dialysis patients
Microvasculopathy
Screening of diabetes in non-diabetic Inadequate evidence
patients with CKD
1559
risk of developing diabetes. Future research is warranted to evaluate
the utility of serum GA in the screening for diabetes, especially in pa-
tients with CKD.
4.2. Bone metabolism
Patients with type 1 and 2 diabetes mellitus are known to have a
higher rate of bone fractures [82]. The proposed mechanism for this
is osteoblast dysfunction due to poor glycemic control. Hyperglyce-
mia impairs osteoblast-like MG-63 cell proliferation [83], osteoblast
responses to parathyroid hormone [84], and reduces 1,25(OH)2D3
[85]. A study in diabetic HD patients revealed that improvements in
glycemic control protect patients against bone loss at the calcaneus
[86]. Furthermore, lower plasma glucose and GA values, but not
HbA1c, were associated with improved bone mineral density at the
calcaneus.
4.3. Diabetic nephropathy and contrast-induced acute kidney injury
Oxidative stress is a major player in the pathogenesis of diabetic
nephropathy [72], as well as in acute renal ischemia during
contrast-induced acute kidney injury [87–90]. GA increases intracel-
lular oxidative products in glomerular mesangial and epithelial cells
[91], suggesting that it may also be involved in the deterioration of
renal function in CKD. Elevated GA values also independently corre-
late with renal dysfunction in non-diabetic patients [92]. In diabetic
patient with moderate to severe renal insufficiency undergoing coro-
nary angiography, GA predicts the development of contrast-induced
acute kidney injury [93]. Therefore, GA may also be a useful biomark-
er in diabetic nephropathy and contrast-induced acute kidney injury.
5. Conclusions
GA reflects short-term glycemic status and is useful for monitoring
glycemic control in patients with wide variations in glucose or when
HbA1c is not reliable. Accumulating evidence suggests that, in diabet-
ic patients with advanced CKD or on dialysis, GA could be a better gly-
cemic index and prognostic factor than HbA1C. However, data are
limited on the utility of GA in earlier stages of CKD and in patients
on PD. Meanwhile, GA may not be a suitable measure in patients
with altered albumin turnover, such as those with nephrotic-range
proteinuria or liver cirrhosis. To utilize the advantages of GA over
HbA1c in the clinical management of diabetic patients with CKD,
guidelines should be established, which include the indications for
the use of GA in glucose monitoring (i.e. who should be tested and
how frequent), the optimal ranges of GA in different ethnic
populations, the corresponding average glucose concentrations,
assay standardization, performance in predicting risk of complica-
tions, and cost-benefit analysis. Furthermore, beyond glycemic con-
trol, the pathological role of GA in macro- or micro-angiopathy is
worth exploring. Interventional studies could use GA as a therapeutic
target or marker to improve prognosis in patients with CKD with or
without diabetes.
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