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Association of glycated albumin, but not glycated hemoglobin, with peripheral vascular calcification in hemodialysis patients with type 2 diabetes
Life Sciences 83 (2008) 516–519
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Life Sciences j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / l i f e s c i e
Association of glycated albumin, but not glycated hemoglobin, with peripheral vascular calcification in hemodialysis patients with type 2 diabetes Shinsuke Yamada a, Masaaki Inaba a,⁎, Kaori Shidara a, Shigeki Okada b, Masanori Emoto a, Eiji Ishimura a, Yoshiki Nishizawa a a
Department of Metabolism, Endocrinology and Molecular Medicine, Internal Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan Okada Clinic, 16-10, Horikoshi-cho, Tennoji-ku, Osaka 543-0056, Japan
b
a r t i c l e
i n f o
Article history: Received 3 June 2008 Accepted 2 August 2008 Keywords: Glycated albumin Glycated hemoglobin Diabetes mellitus Vascular calcification Hemodialysis
a b s t r a c t Aims: Elevated HbA1C is a predictor of mortality as well as peripheral vascular calcification in hemodialysis (HD) patients with diabetes. However, improved glycemic control as reflected by reduction in HbA1C may dismiss the relationship between HbA1C and mortality in those patients, due possibly to the underestimation of HbA1C by erythropoietin use. This study was to establish the significance of glycated albumin (GA) as a useful marker of peripheral vascular calcification in diabetic HD patients, in comparison with HbA1C. Main methods: We examined 49 HD patients with type 2 diabetes (37 men and 12 women). Peripheral vascular calcification at hand arteries was checked on a simple X-ray photograph. GA and HbA1C were determined just before HD session. Key findings: The prevalence of peripheral vascular calcification was significantly higher in diabetic patients (65.3%) than in non-diabetic patients (27.0%). Multiple regression analyses in diabetic patients showed that both HD duration and GA were significantly associated with the presence of peripheral vascular calcification. When GA was replaced by HbA1C in the same model, HbA1C failed to show a significant association. However, when a weekly dose of erythropoietin was simultaneously included in addition to HD duration and HbA1C, both HbA1C as well as HD duration emerged as a significant factor associated with the presence of peripheral vascular calcification. Significance: The present study suggested that GA might be a better indicator of glycemic control, and raise the possibility that improvement of glycemic control might prevent against the development of peripheral vascular calcification in diabetic HD patients. © 2008 Published by Elsevier Inc.
Introduction Vascular calcification increases cardiovascular and other causes of mortality (Lehto et al., 1996; Davies and Hruska, 2001), and is highly prevalent in dialysis patients. Factors affecting vascular calcification in dialysis patients include advanced age, derangement of calcium-phosphate metabolism (Davies and Hruska, 2001; Cozzolino et al., 2001; Goodman and Salusky, 2001), and diabetes (O'Hare et al., 2002; Raggi et al., 2002; Cheung et al., 2000). We have reported that the factors affecting peripheral vascular calcification differ between hemodialysis (HD) patients with and without diabetes, and that poor glycemic control, as reflected by increased HbA1C, is the strongest predictor of vascular calcification in diabetic HD patients (Ishimura et al., 2002). HbA1C is also a good
⁎ Corresponding author. Tel.: +81 6 6645 3806; fax: +81 6 6645 3808. E-mail address: [email protected] (M. Inaba). 0024-3205/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.lfs.2008.08.001
predictor for mortality in diabetic HD patients with high HbA1C (Wu et al., 1997; Morioka et al., 2001), although improved glycemic control dismiss the significance of HbA1C as a significant predictor in those patients having lower values of HbA 1C (Williams et al., 2006). We recently showed that glycemic control assessed by HbA1C in these patients may be underestimated due to an increased proportion of younger erythrocytes produced by erythropoietin use (Inaba et al., 2007). Particularly in those with lower HbA1C values, the influence of erythropoietin to induce false-reduction of HbA1C might be augmented. We found that glycated albumin (GA), which is independent of erythropoietin use, gives a significantly better estimate of glycemic control in diabetic HD patients (Inaba et al., 2007; Kumeda et al., in press). The present study was performed to establish the significance of GA, in comparison with HbA1C, as a useful marker of peripheral vascular calcification in diabetic HD patients having better glycemic control.
S. Yamada et al. / Life Sciences 83 (2008) 516–519
Subjects and methods
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Table 2 Multiple regression analysis of factors independently associated with the presence of vascular calcification in 123 HD patients
Subjects
Presence of vascular calcification
One hundred twenty three HD patients, including 49 with type 2 diabetes and 74 without, were enrolled in the study from April to June in 2007 in Okada Clinic, Osaka, Japan. All patients provided written informed consent before participation in this study, which was approved by institutional ethics committees (Osaka City University Graduate School of Medicine) and was conducted in accordance with the principles of the Declaration of Helsinki. Diabetic patients included 37 men and 12 women, and their ages ranged from 33 to 80 years old (62.3 ± 10.3; mean ± SD). Of the 49 diabetic patients, 20 were treated with insulin, 4 with oral anti-diabetic drugs, and 25 with diet only. The non-diabetic patients included 45 men and 29 women, and their ages ranged from 23 to 84 years old (55.5 ± 14.7). Sample collection From April to June in 2007, hand roentgenography was carried out in each patient at a voltage of 50 kV (100 mA, 0.03 s). Vascular calcification of the hand arteries distal to the wrist joints was evaluated by one of the authors (S.Y.) who was blinded to other patient data. Blood was taken just before the HD session under nonfasting conditions to measure casual plasma glucose (PG), GA, HbA1C and other serum parameters. Measurements of GA and HBA1C GA and HbA1C were measured as described previously. Briefly, GA was measured by an enzymatic method using the Lucica® GA-L kit (Asahi Kasei Pharma Corp., Tokyo, Japan) (Kouzuma et al., 2004). GA was hydrolyzed to amino acids by an albumin-specific proteinase and then oxidized by ketoamine oxidase to produce hydrogen peroxide, which was measured quantitatively. The GA value was calculated as the percentage of glycated albumin relative to total albumin, which was measured in the same serum sample using a new bromocresol purple method (Kouzuma et al., 2004). The GA assay is not influenced by the physiological concentrations of ascorbic acid, bilirubin, or glucose up to 1000 mg/dl. HbA1C was measured by routine HPLC, which was standardized according to the Japan Diabetes Society (Tominaga et al., 2005).
Presence of diabetes Age Gender BMI Systolic blood pressure HD duration Corrected calcium Creatinine R2
ß
p
0.553 0.026 −0.178 −0.118 −0.121 0.316 0.031 0.192 0.336‡
b 0.0001‡ 0.7652 0.0345§ 0.1508 0.1382 0.0004† 0.7070 0.0369§
Values are standard regression coefficients (ß). R 2 = multiple coefficient of determination. ‡p b 0.0001, †p b 0.001, §p b 0.05. Presence of vascular calcification: (−) = 0, (+) = 1. Presence of diabetes: no diabetes = 1, diabetes = 2. Gender: male = 1, female = 2.
Biochemical measurements To measure serum parameters in HD patients, blood was drawn immediately before the morning Monday/Tuesday session of HD without overnight fasting, as described previously (Inaba et al., 2002). The mean values of three casual monthly measurements of PG obtained during the 2 months prior to determination of serum GA and HbA1C were used in the analysis. Serum GA and HbA1C were measured once, as also described previously (Inaba et al., 2007). Statistical analysis Data are expressed as means ± SD. Correlation coefficients were calculated by simple regression analysis, and differences in means between the two groups were analyzed by Student t test. Multivariate regression analyses were performed to explore the association of plasma glucose, GA, and HbA1C with peripheral vascular calcification. All analyses were performed using StatView 5 statistical software for Windows (SAS Institute Inc., Cary, NC, USA). Results Clinical characteristics of subjects
Table 1 Clinical characteristics of 49 diabetic HD patients Number
49
Age (years) Gender (male/female) BMI (kg/m2) Systolic blood pressure (mm Hg) Smoker/non-smoker HD duration (months) CTR (%) Erythropoietin use/non-use Dose of erythropoietin (U/week) Creatinine (mg/dl) Hemoglobin (mg/dl) Total cholesterol (mg/dl) Albumin (g/dl) Corrected calcium (mg/dl) Phosphate (mg/dl) Calcium-phosphorus product Intact PTH (ng/l) Casual plasma glucose (mg/dl) Glycated albumin (%) HbA1C (%)
62.3 ± 10.3 37/12 22.5 ± 3.3 169.2 ± 17.7 18/31 59.8 ± 39.5 49.2 ± 4.6 43/6 4668.4 ± 3020.5 10.2 ± 2.6 10.6 ± 1.0 162.8 ± 31.4 3.9 ± 0.3 9.2 ± 0.7 5.1 ± 1.2 46.6 ± 12.3 205.9 ± 100.8 178.9 ± 77.0 24.5 ± 8.4 5.9 ± 1.3
Data are expressed as means ± SD.
The clinical characteristics of diabetic HD patients are shown in Table 1. As parameters for assessment of glycemic control, casual PG, GA, and HbA1C in DM patients were 178.9 ± 77.0 mg/dl, 24.5 ± 8.4%, and 5.9 ± 1.3%, respectively, suggesting that glycemic control of diabetic HD patients were rather good. Calcification in the hand artery Thirty two out of the 49 (65.3%) diabetic HD patients had vascular calcification in the hand artery, which was significantly higher than the 27.4% in non-diabetic HD patients, as we previously reported (Ishimura et al., 2002). Multivariate logistic regression analyses to explore factors affecting vascular calcification clearly showed that the presence of diabetes is positively associated with the occurrence of vascular calcification (Table 2). Diabetic HD patients with and without vascular calcification Among various parameters, HD duration was significantly longer in diabetic HD patients with hand-artery calcification than those without. In terms of 3 markers for glycemic control, GA was significantly higher in the former than in the latter group of patients. In contrast,
518
S. Yamada et al. / Life Sciences 83 (2008) 516–519
Table 3 Clinical characteristics of 49 HD patients with diabetes Vascular calcification
(+)
(−)
p
Number Age (years) Gender (male/female) BMI (kg/m2) Systolic blood pressure (mmHg) Smoker/non-smoker HD duration (months) CTR (%) Erythropoietin use/non-use Erythropoietin dose (U/week) Creatinine (mg/dl) Hemoglobin (mg/dl) Total cholesterol (mg/dl) Albumin (g/dl) Corrected calcium (mg/dl) Phosphate (mg/dl) Calcium-phosphorus product Intact PTH (ng/l) Casual plasma glucose (mg/dl) Glycated albumin (%) HbA1C (%)
32 60.6 ± 10.0 26/6 22.1 ± 3.0 168.7 ± 17.0 19/13 72.9 ± 38.9 49.5 ± 5.0 29/3 4898.4 ± 2920.2 10.8 ± 2.5 10.7 ± 1.1 156.9 ± 30.6 3.9 ± 0.3 9.2 ± 0.7 5.1 ± 1.2 47.1 ± 12.8 213.4 ± 97.8 174.3 ± 69.7 26.4 ± 8.9 6.1 ± 1.5
17 65.7 ± 10.3 11/6 23.2 ± 3.9 170.2 ± 19.5 12/5 35.2 ± 27.6 48.6 ± 4.0 14/3 4235.3 ± 3247.0 9.0 ± 2.6 10.4 ± 0.9 173.8 ± 30.7 3.8 ± 0.4 9.1 ± 0.7 5.0 ± 1.2 45.7 ± 11.6 191.7 ± 107.8 187.6 ± 90.9 20.8 ± 6.0 5.5 ± 0.7
– 0.1045 0.2079 0.3128 0.7701 0.4488 0.0009† 0.5232 0.4110 0.4703 0.0253§ 0.3254 0.0728⁎ 0.1579 0.5063 0.8749 0.7086 0.4794 0.5685 0.0249§ 0.0908⁎
Data are expressed as means ± SD. †p b 0.001, §p b 0.05, ⁎p b 0.1.
casual PG and HbA1C did not differ significantly between the two groups of patients (Table 3). Factors associated with hand-artery calcification in diabetic HD patients The results of multiple regression analyses to explore the effect of GA, HbA1C, and other factors associated with vascular calcification of the hand artery in diabetic HD patients are shown in Table 4. The independent variables were selected based on parameters that differed between diabetic HD patients with and without hand-artery calcification. In Model 1, which included HD duration and GA, both variables were significantly and independently associated with handartery calcification. In Model 2, which included HbA1C in place of GA, HbA1C failed to emerge as a significant and independent factor. The weekly dose of erythropoietin was added to Models 1 and 2 to give Models 3 and 4, respectively, and the association of HbA1C with handartery calcification became statistically significant in Model 4. Discussion In the present study, we confirmed our previous findings (Ishimura et al., 2002; Shoji et al., 2001; Inaba et al., 2006) that diabetic HD patients have an increased prevalence of peripheral hand-artery calcification, and we demonstrated that GA is significantly and independently associated in a positive manner with the occurrence of hand-artery calcification in diabetic HD patients, whereas HbA1C is not associated with this condition (Table 4). Of particular interest, HbA1C emerged as a significant factor associated with peripheral artery calcification when the weekly dose of erythropoietin was included as an independent variable. We have previously shown that HbA1C is significantly associated with peripheral vascular calcification of the hand artery in diabetic HD patients with a high HbA1C of approximately 7.0% (Ishimura et al., 2002), but not in those with lower HbA1C values of approximately 5.8% (Inaba et al., 2006). Since the mean value of HbA1C in the diabetic HD patients in the present study was 5.9 ± 1.3%, the current data are consistent with our earlier report suggesting that improved glycemic control might dismiss a significant association between HbA1c and peripheral vascular calcification in diabetic HD patients. We have also reported (Inaba et al., 2007) that HbA1C is reduced by erythropoietin injection independent of glycemic control in diabetic
HD patients, and thus that GA is more relevant than HbA1C for assessing glycemic control in those patients. Of great interest, after adjustment for the erythropoietin dose did HbA1C emerge as a significant factor associated with peripheral artery calcification even in diabetic HD patients with lower HbA1C values. These data suggest that improvement of glycemic control might prevent development of peripheral artery calcification in diabetic HD patients, and that GA provide better assay for glycemic control in that GA, in contrast to HbA1c, might be independent of erythropoietin injection in these patients. The influence of erythropoietin on HbA1C values was again evident by the data that the adjustment for the erythropoietin dose made the association of HbA1C with hand-artery calcification statistically significant even in patients with better glycemic control (Table 4). In our recent report, erythropoietin injection, in addition to casual PG, emerged as an independent factor associated with HbA1C in diabetic HD patients (Inaba et al., 2007). Increasing the erythropoietin dose causes a corresponding fall in hematocrit, and this has been shown to lower HbA1C even under the stable PG levels (Nakao et al., 1998). Since about 90% of diabetic HD patients receive erythropoietin in Japanese HD patients, the assessment of glycemic control using HbA1C gives a significant underestimation of glycemic control by an average of 33% (Inaba et al., 2007). Therefore, the HbA1C value may not be associated with hand-artery calcification due to its apparent modulation by erythropoietin, independently of glycemic control. Taking these data collectively, as glycemic control improves in diabetic HD patients, the rate of peripheral artery calcification might be reduced. Calcification of the hand arteries affects the medial layer and is of the type found in Moenckeberg's sclerosis (Edmonds, 2000; Cao et al., 2005). In contrast to the significant effect of calciumphosphate product on development of hand-artery calcification in non-diabetic HD patients, diabetic HD patients exhibit increased hand-artery calcification independently of the calcium-phosphate product (Ishimura et al., 2002). Increased hand-artery calcification seems to be associated with poor glycemic control, as reflected by the association with GA and HbA1C. Low bone turnover has also been associated with vascular calcification in diabetic HD patients (Galassi et al., 2006), and poor glycemic control induces low bone turnover by suppressing PTH secretion (Sugimoto et al., 1990), impairing osteoblast growth (Inaba et al., 1999), and reducing the responsiveness of osteoblasts to PTH (Inaba et al., 2002) and 1,25dihydroxyvitamin D3 (Inaba et al., 1999). A direct adverse effect of high glucose on vascular cells has also been proposed (Wadham et al., 2007; Srivastava et al., 2006). The mean values of monthly PG were essentially the same throughout the study period (data not shown), suggesting that glycemic control was stable during the preceding two months before determination of GA and HbA1C and that a single determination just
Table 4 Multiple regression analysis of factors independently associated with the presence of vascular calcification in 49 HD patients with diabetes Presence of vascular calcification
HD duration Erythropoietin dose Glycated albumin HbA1C R2
Model 1
Model 2
Model 3
Model 4
ß
P
ß
P
ß
p
ß
p
0.434
0.0011†
0.459
0.0007†
0.426 0.035
0.0019§ 0.7867
0.440 0.091
0.0014§ 0.5017
0.283
0.0283§
0.285
0.0290§
0.289†
0.245 0.0578⁎ 0.270†
0.290§
0.270 0.0465§ 0.277§
Values are standard regression coefficients (ß). R 2 = multiple coefficient of determination. †p b 0.001, §p b 0.05, ⁎p b 0.1. Presence of vascular calcification: (−) = 0, (+) = 1.
S. Yamada et al. / Life Sciences 83 (2008) 516–519
before the Monday/Tuesday hemodialysis session was representative of glycemic control in diabetic HD patients. HbA1C and GA reflect glycemic control over the preceding 4 to 6 weeks and 1 to 2 weeks (Tahara, 2000), respectively, and stable glycemic control during the preceding 2 months could negate the impact of acute changes assessed by HbA1C and GA in the present study, as previously described (Inaba et al., 2007). Glycated albumin acquires biological properties that are linked to the pathogenesis of diabetic vascular complications (Kennedy and Merimee, 1981; Cohen et al., 2006), suggesting that GA might contribute directly to vascular injury. As such, GA is better than HbA1C to associate with the development of vascular complications in diabetic HD patients. However, there is also a limitation to the GA assay, since albumin turnover is likely to change in patients who are maintained on peritoneal dialysis or have chronic renal failure with massive proteinuria. In such patients, GA values would theoretically be reduced due to shorter exposure to plasma albumin. Within this limitation, we suggest that GA provides a significantly better measure to reflect peripheral vascular calcification in diabetic HD patients, and that improvement of glycemic control might prevent development of vascular calcification in these patients. Conclusion The present study suggested that GA might be a better indicator of glycemic control in diabetic HD patients, and raise the possibility that improvement of glycemic control might prevent against the development of peripheral vascular calcification in those patients. References Cao, J.J., Hudson, M., Jankowski, M., Whitehouse, F., Weaver, W.D., 2005. Relation of chronic and acute glycemic control on mortality in acute myocardial infarction with diabetes mellitus. The American Journal of Cardiology 96 (2), 183–186. Cheung, A.K., Sarnak, M.J., Yan, G., Dwyer, J.T., Heyka, R.J., Rocco, M.V., Teehan, B.P., Levey, A.S., 2000. Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients. Kidney International 58 (1), 353–362. Cohen, M.P., Ziyadeh, F.N., Chen, S., 2006. Amadori-modified glycated serum proteins and accelerated atherosclerosis in diabetes: pathogenic and therapeutic implications. The Journal of Laboratory and Clinical Medicine 147 (5), 211–219. Cozzolino, M., Dusso, A.S., Slatopolsky, E., 2001. Role of calcium-phosphate product and bone-associated proteins on vascular calcification in renal failure. Journal of the American Society of Nephrology 12 (11), 2511–2516. Davies, M.R., Hruska, K.A., 2001. Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kidney International 60 (2), 472–479. Edmonds, M.E., 2000. Medial arterial calcification and diabetes mellitus. Zeitschrift fur Kardiologie 89 (2), 101–104. Galassi, A., Spiegel, D.M., Bellasi, A., Block, G.A., Raggi, P., 2006. Accelerated vascular calcification and relative hypoparathyroidism in incident haemodialysis diabetic patients receiving calcium binders. Nephrology, Dialysis, Transplantation 21 (11), 3215–3222. Goodman, W.G., Salusky, I.B., 2001. Non-invasive assessments of cardiovascular disease in patients with renal failure. Current Opinion in Nephrology and Hypertension 10 (3), 365–369. Inaba, M., Nishizawa, Y., Mita, K., Kumeda, Y., Emoto, M., Kawagishi, T., Ishimura, E., Nakatsuka, K., Shioi, A., Morii, H., 1999. Poor glycemic control impairs the response of biochemical parameters of bone formation and resorption to exogenous 1,25-dihydroxyvitamin D3 in patients with type 2 diabetes. Osteoporosis International 9 (6), 525–531. Inaba, M., Nagasue, K., Okuno, S., Ueda, M., Kumeda, Y., Imanishi, Y., Shoji, T., Ishimura, E., Ohta, T., Nakatani, T., Kim, M., Nishizawa, Y., 2002. Impaired secretion of
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parathyroid hormone, but not refractoriness of osteoblast, is a major mechanism of low bone turnover in hemodialyzed patients with diabetes mellitus. American Journal of Kidney Diseases 39 (6), 1261–1269. Inaba, M., Okuno, S., Imanishi, Y., Yamada, S., Shioi, A., Yamakawa, T., Ishimura, E., Nishizawa, Y., 2006. Role of fibroblast growth factor-23 in peripheral vascular calcification in non-diabetic and diabetic hemodialysis patients. Osteoporosis International 17 (10), 1506–1513. Inaba, M., Okuno, S., Kumeda, Y., Yamada, S., Imanishi, Y., Tabata, T., Okamura, M., Okada, S., Yamakawa, T., Ishimura, E., Nishizawa, Y., 2007. Glycated albumin is a better glycemic indicator than glycated hemoglobin values in diabetic hemodialysis patients: effect of anemia and erythropoietin injection. Journal of the American Society of Nephrology 18 (3), 896–903. Ishimura, E., Okuno, S., Kitatani, K., Kim, M., Shoji, T., Nakatani, T., Inaba, M., Nishizawa, Y., 2002. Different risk factors for peripheral vascular calcification between diabetic and non-diabetic hemodialysis patients—importance of glycaemic control. Diabetologia 45 (10), 1446–1448. Kennedy, A.L., Merimee, T.J., 1981. Glycosylated serum protein and hemoglobin A1 levels to measure control glycemia. Annals of Internal Medicine 95 (1), 56–58. Kouzuma, T., Uematsu, Y., Usami, T., Imamura, S., 2004. Study of glycated amino acid elimination for an improved enzymatic glycated albumin measurement method. Clinica Chimica Acta 346 (2), 135–143. Kumeda, Y., Inaba, M., Shoj, S., Ishimura, E., Inariba, H., Yabe, S., Okamura, M., Nishizawa, Y., in press. Significant correlation of glycated albumin, but not glycated haemoglobin, with arterial stiffening in haemodialysis patients with type 2 diabetes. Clinical Endocrinology. Lehto, S., Niskanen, L., Suhonen, M., Ronnemaa, T., Laakso, M., 1996. Medial artery calcification. A neglected harbinger of cardiovascular complication in non-insulindependent diabetes mellitus. Arteriosclerosis, Thrombosis, and Vascular Biology 16 (8), 978–983. Morioka, T., Emoto, M., Tabata, T., Shoji, T., Tahara, H., Kishimoto, H., Ishimura, E., Nishizawa, Y., 2001. Glycemic control is a predictor of survival for diabetic patients on hemodialysis. Diabetes Care 24 (5), 909–913. Nakao, T., Matsumoto, H., Okada, T., Han, M., Hidaka, H., Yoshino, M., Shino, T., Yamada, C., Nagaoka, Y., 1998. Influence of erythropoietin treatment on hemoglobin A1c levels in patients with chronic renal failure on hemodialysis. Internal Medcine 37 (10), 826–830. O'Hare, A.M., Hsu, C.Y., Bacchetti, P., Johansen, K.L., 2002. Peripheral vascular disease risk factors among patients undergoing hemodialysis. Journal of the American Society of Nephrology 13 (2), 497–503. Raggi, P., Boulay, A., Chasan-Taber, S., Amin, N., Dillon, M., Burke, S.K., Chertow, G.M., 2002. Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease? Journal of the American College of Cardiology 39 (4), 695–701. Shoji, T., Emoto, M., Shinohara, K., Kakiya, R., Tsujimoto, Y., Kishimoto, H., Ishimura, E., Tabata, T., Nishizawa, Y., 2001. Diabetes mellitus, aortic stiffness, and cardiovascular mortality in end-stage renal disease. Journal of the American Society of Nephrology 12 (10), 2117–2124. Srivastava, S., Ramana, K.V., Tammali, R., Srivastava, S.K., Bhatnagar, A., 2006. Contribution of aldose reductase to diabetic hyperproliferation of vascular smooth muscle cells. Diabetes 55 (4), 901–910. Sugimoto, T., Ritter, C., Morrissey, J., Hayes, C., Slatopolsky, E., 1990. Effects of high concentrations of glucose on PTH secretion in parathyroid cells. Kidney International 37 (6), 1522–1527. Tahara, Y., 2000. Glycoalbumin. Kettouti wo Miru, Kangaeru, pp. 62–69 (In Japanese). Tominaga, M., Makino, H., Yoshino, G., Kuwa, K., Takei, I., Aono, Y., Hoshino, T., Umemoto, M., Shimatsu, A., Sanke, T., Kuwashima, M., Taminato, T., Ono, J., 2005. Japanese standard reference material JDS Lot 2 for haemoglobin A1c. II: present state of standardization of haemoglobin A1c in Japan using the new reference material in routine clinical assays. Annals of Clinical Biochemistry 42 (Pt 1), 47–50. Wadham, C., Parker, A., Wang, L., Xia, P., 2007. High glucose attenuates protein Snitrosylation in endothelial cells: role of oxidative stress. Diabetes 56 (11), 2715–2721. Williams, M.E., Lacson Jr, E., Teng, M., Ofsthun, N., Lazarus, J.M., 2006. Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival. Kidney International 70 (8), 1503–1509. Wu, M.S., Yu, C.C., Yang, C.W., Wu, C.H., Haung, J.Y., Hong, J.J., Fan Chiang, C.Y., Huang, C.C., Leu, M.L., 1997. Poor pre-dialysis glycaemic control is a predictor of mortality in type II diabetic patients on maintenance haemodialysis. Nephrology, Dialysis, Transplantation 12 (10), 2105–2110.
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Life Sciences j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / l i f e s c i e
Association of glycated albumin, but not glycated hemoglobin, with peripheral vascular calcification in hemodialysis patients with type 2 diabetes Shinsuke Yamada a, Masaaki Inaba a,⁎, Kaori Shidara a, Shigeki Okada b, Masanori Emoto a, Eiji Ishimura a, Yoshiki Nishizawa a a
Department of Metabolism, Endocrinology and Molecular Medicine, Internal Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan Okada Clinic, 16-10, Horikoshi-cho, Tennoji-ku, Osaka 543-0056, Japan
b
a r t i c l e
i n f o
Article history: Received 3 June 2008 Accepted 2 August 2008 Keywords: Glycated albumin Glycated hemoglobin Diabetes mellitus Vascular calcification Hemodialysis
a b s t r a c t Aims: Elevated HbA1C is a predictor of mortality as well as peripheral vascular calcification in hemodialysis (HD) patients with diabetes. However, improved glycemic control as reflected by reduction in HbA1C may dismiss the relationship between HbA1C and mortality in those patients, due possibly to the underestimation of HbA1C by erythropoietin use. This study was to establish the significance of glycated albumin (GA) as a useful marker of peripheral vascular calcification in diabetic HD patients, in comparison with HbA1C. Main methods: We examined 49 HD patients with type 2 diabetes (37 men and 12 women). Peripheral vascular calcification at hand arteries was checked on a simple X-ray photograph. GA and HbA1C were determined just before HD session. Key findings: The prevalence of peripheral vascular calcification was significantly higher in diabetic patients (65.3%) than in non-diabetic patients (27.0%). Multiple regression analyses in diabetic patients showed that both HD duration and GA were significantly associated with the presence of peripheral vascular calcification. When GA was replaced by HbA1C in the same model, HbA1C failed to show a significant association. However, when a weekly dose of erythropoietin was simultaneously included in addition to HD duration and HbA1C, both HbA1C as well as HD duration emerged as a significant factor associated with the presence of peripheral vascular calcification. Significance: The present study suggested that GA might be a better indicator of glycemic control, and raise the possibility that improvement of glycemic control might prevent against the development of peripheral vascular calcification in diabetic HD patients. © 2008 Published by Elsevier Inc.
Introduction Vascular calcification increases cardiovascular and other causes of mortality (Lehto et al., 1996; Davies and Hruska, 2001), and is highly prevalent in dialysis patients. Factors affecting vascular calcification in dialysis patients include advanced age, derangement of calcium-phosphate metabolism (Davies and Hruska, 2001; Cozzolino et al., 2001; Goodman and Salusky, 2001), and diabetes (O'Hare et al., 2002; Raggi et al., 2002; Cheung et al., 2000). We have reported that the factors affecting peripheral vascular calcification differ between hemodialysis (HD) patients with and without diabetes, and that poor glycemic control, as reflected by increased HbA1C, is the strongest predictor of vascular calcification in diabetic HD patients (Ishimura et al., 2002). HbA1C is also a good
⁎ Corresponding author. Tel.: +81 6 6645 3806; fax: +81 6 6645 3808. E-mail address: [email protected] (M. Inaba). 0024-3205/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.lfs.2008.08.001
predictor for mortality in diabetic HD patients with high HbA1C (Wu et al., 1997; Morioka et al., 2001), although improved glycemic control dismiss the significance of HbA1C as a significant predictor in those patients having lower values of HbA 1C (Williams et al., 2006). We recently showed that glycemic control assessed by HbA1C in these patients may be underestimated due to an increased proportion of younger erythrocytes produced by erythropoietin use (Inaba et al., 2007). Particularly in those with lower HbA1C values, the influence of erythropoietin to induce false-reduction of HbA1C might be augmented. We found that glycated albumin (GA), which is independent of erythropoietin use, gives a significantly better estimate of glycemic control in diabetic HD patients (Inaba et al., 2007; Kumeda et al., in press). The present study was performed to establish the significance of GA, in comparison with HbA1C, as a useful marker of peripheral vascular calcification in diabetic HD patients having better glycemic control.
S. Yamada et al. / Life Sciences 83 (2008) 516–519
Subjects and methods
517
Table 2 Multiple regression analysis of factors independently associated with the presence of vascular calcification in 123 HD patients
Subjects
Presence of vascular calcification
One hundred twenty three HD patients, including 49 with type 2 diabetes and 74 without, were enrolled in the study from April to June in 2007 in Okada Clinic, Osaka, Japan. All patients provided written informed consent before participation in this study, which was approved by institutional ethics committees (Osaka City University Graduate School of Medicine) and was conducted in accordance with the principles of the Declaration of Helsinki. Diabetic patients included 37 men and 12 women, and their ages ranged from 33 to 80 years old (62.3 ± 10.3; mean ± SD). Of the 49 diabetic patients, 20 were treated with insulin, 4 with oral anti-diabetic drugs, and 25 with diet only. The non-diabetic patients included 45 men and 29 women, and their ages ranged from 23 to 84 years old (55.5 ± 14.7). Sample collection From April to June in 2007, hand roentgenography was carried out in each patient at a voltage of 50 kV (100 mA, 0.03 s). Vascular calcification of the hand arteries distal to the wrist joints was evaluated by one of the authors (S.Y.) who was blinded to other patient data. Blood was taken just before the HD session under nonfasting conditions to measure casual plasma glucose (PG), GA, HbA1C and other serum parameters. Measurements of GA and HBA1C GA and HbA1C were measured as described previously. Briefly, GA was measured by an enzymatic method using the Lucica® GA-L kit (Asahi Kasei Pharma Corp., Tokyo, Japan) (Kouzuma et al., 2004). GA was hydrolyzed to amino acids by an albumin-specific proteinase and then oxidized by ketoamine oxidase to produce hydrogen peroxide, which was measured quantitatively. The GA value was calculated as the percentage of glycated albumin relative to total albumin, which was measured in the same serum sample using a new bromocresol purple method (Kouzuma et al., 2004). The GA assay is not influenced by the physiological concentrations of ascorbic acid, bilirubin, or glucose up to 1000 mg/dl. HbA1C was measured by routine HPLC, which was standardized according to the Japan Diabetes Society (Tominaga et al., 2005).
Presence of diabetes Age Gender BMI Systolic blood pressure HD duration Corrected calcium Creatinine R2
ß
p
0.553 0.026 −0.178 −0.118 −0.121 0.316 0.031 0.192 0.336‡
b 0.0001‡ 0.7652 0.0345§ 0.1508 0.1382 0.0004† 0.7070 0.0369§
Values are standard regression coefficients (ß). R 2 = multiple coefficient of determination. ‡p b 0.0001, †p b 0.001, §p b 0.05. Presence of vascular calcification: (−) = 0, (+) = 1. Presence of diabetes: no diabetes = 1, diabetes = 2. Gender: male = 1, female = 2.
Biochemical measurements To measure serum parameters in HD patients, blood was drawn immediately before the morning Monday/Tuesday session of HD without overnight fasting, as described previously (Inaba et al., 2002). The mean values of three casual monthly measurements of PG obtained during the 2 months prior to determination of serum GA and HbA1C were used in the analysis. Serum GA and HbA1C were measured once, as also described previously (Inaba et al., 2007). Statistical analysis Data are expressed as means ± SD. Correlation coefficients were calculated by simple regression analysis, and differences in means between the two groups were analyzed by Student t test. Multivariate regression analyses were performed to explore the association of plasma glucose, GA, and HbA1C with peripheral vascular calcification. All analyses were performed using StatView 5 statistical software for Windows (SAS Institute Inc., Cary, NC, USA). Results Clinical characteristics of subjects
Table 1 Clinical characteristics of 49 diabetic HD patients Number
49
Age (years) Gender (male/female) BMI (kg/m2) Systolic blood pressure (mm Hg) Smoker/non-smoker HD duration (months) CTR (%) Erythropoietin use/non-use Dose of erythropoietin (U/week) Creatinine (mg/dl) Hemoglobin (mg/dl) Total cholesterol (mg/dl) Albumin (g/dl) Corrected calcium (mg/dl) Phosphate (mg/dl) Calcium-phosphorus product Intact PTH (ng/l) Casual plasma glucose (mg/dl) Glycated albumin (%) HbA1C (%)
62.3 ± 10.3 37/12 22.5 ± 3.3 169.2 ± 17.7 18/31 59.8 ± 39.5 49.2 ± 4.6 43/6 4668.4 ± 3020.5 10.2 ± 2.6 10.6 ± 1.0 162.8 ± 31.4 3.9 ± 0.3 9.2 ± 0.7 5.1 ± 1.2 46.6 ± 12.3 205.9 ± 100.8 178.9 ± 77.0 24.5 ± 8.4 5.9 ± 1.3
Data are expressed as means ± SD.
The clinical characteristics of diabetic HD patients are shown in Table 1. As parameters for assessment of glycemic control, casual PG, GA, and HbA1C in DM patients were 178.9 ± 77.0 mg/dl, 24.5 ± 8.4%, and 5.9 ± 1.3%, respectively, suggesting that glycemic control of diabetic HD patients were rather good. Calcification in the hand artery Thirty two out of the 49 (65.3%) diabetic HD patients had vascular calcification in the hand artery, which was significantly higher than the 27.4% in non-diabetic HD patients, as we previously reported (Ishimura et al., 2002). Multivariate logistic regression analyses to explore factors affecting vascular calcification clearly showed that the presence of diabetes is positively associated with the occurrence of vascular calcification (Table 2). Diabetic HD patients with and without vascular calcification Among various parameters, HD duration was significantly longer in diabetic HD patients with hand-artery calcification than those without. In terms of 3 markers for glycemic control, GA was significantly higher in the former than in the latter group of patients. In contrast,
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S. Yamada et al. / Life Sciences 83 (2008) 516–519
Table 3 Clinical characteristics of 49 HD patients with diabetes Vascular calcification
(+)
(−)
p
Number Age (years) Gender (male/female) BMI (kg/m2) Systolic blood pressure (mmHg) Smoker/non-smoker HD duration (months) CTR (%) Erythropoietin use/non-use Erythropoietin dose (U/week) Creatinine (mg/dl) Hemoglobin (mg/dl) Total cholesterol (mg/dl) Albumin (g/dl) Corrected calcium (mg/dl) Phosphate (mg/dl) Calcium-phosphorus product Intact PTH (ng/l) Casual plasma glucose (mg/dl) Glycated albumin (%) HbA1C (%)
32 60.6 ± 10.0 26/6 22.1 ± 3.0 168.7 ± 17.0 19/13 72.9 ± 38.9 49.5 ± 5.0 29/3 4898.4 ± 2920.2 10.8 ± 2.5 10.7 ± 1.1 156.9 ± 30.6 3.9 ± 0.3 9.2 ± 0.7 5.1 ± 1.2 47.1 ± 12.8 213.4 ± 97.8 174.3 ± 69.7 26.4 ± 8.9 6.1 ± 1.5
17 65.7 ± 10.3 11/6 23.2 ± 3.9 170.2 ± 19.5 12/5 35.2 ± 27.6 48.6 ± 4.0 14/3 4235.3 ± 3247.0 9.0 ± 2.6 10.4 ± 0.9 173.8 ± 30.7 3.8 ± 0.4 9.1 ± 0.7 5.0 ± 1.2 45.7 ± 11.6 191.7 ± 107.8 187.6 ± 90.9 20.8 ± 6.0 5.5 ± 0.7
– 0.1045 0.2079 0.3128 0.7701 0.4488 0.0009† 0.5232 0.4110 0.4703 0.0253§ 0.3254 0.0728⁎ 0.1579 0.5063 0.8749 0.7086 0.4794 0.5685 0.0249§ 0.0908⁎
Data are expressed as means ± SD. †p b 0.001, §p b 0.05, ⁎p b 0.1.
casual PG and HbA1C did not differ significantly between the two groups of patients (Table 3). Factors associated with hand-artery calcification in diabetic HD patients The results of multiple regression analyses to explore the effect of GA, HbA1C, and other factors associated with vascular calcification of the hand artery in diabetic HD patients are shown in Table 4. The independent variables were selected based on parameters that differed between diabetic HD patients with and without hand-artery calcification. In Model 1, which included HD duration and GA, both variables were significantly and independently associated with handartery calcification. In Model 2, which included HbA1C in place of GA, HbA1C failed to emerge as a significant and independent factor. The weekly dose of erythropoietin was added to Models 1 and 2 to give Models 3 and 4, respectively, and the association of HbA1C with handartery calcification became statistically significant in Model 4. Discussion In the present study, we confirmed our previous findings (Ishimura et al., 2002; Shoji et al., 2001; Inaba et al., 2006) that diabetic HD patients have an increased prevalence of peripheral hand-artery calcification, and we demonstrated that GA is significantly and independently associated in a positive manner with the occurrence of hand-artery calcification in diabetic HD patients, whereas HbA1C is not associated with this condition (Table 4). Of particular interest, HbA1C emerged as a significant factor associated with peripheral artery calcification when the weekly dose of erythropoietin was included as an independent variable. We have previously shown that HbA1C is significantly associated with peripheral vascular calcification of the hand artery in diabetic HD patients with a high HbA1C of approximately 7.0% (Ishimura et al., 2002), but not in those with lower HbA1C values of approximately 5.8% (Inaba et al., 2006). Since the mean value of HbA1C in the diabetic HD patients in the present study was 5.9 ± 1.3%, the current data are consistent with our earlier report suggesting that improved glycemic control might dismiss a significant association between HbA1c and peripheral vascular calcification in diabetic HD patients. We have also reported (Inaba et al., 2007) that HbA1C is reduced by erythropoietin injection independent of glycemic control in diabetic
HD patients, and thus that GA is more relevant than HbA1C for assessing glycemic control in those patients. Of great interest, after adjustment for the erythropoietin dose did HbA1C emerge as a significant factor associated with peripheral artery calcification even in diabetic HD patients with lower HbA1C values. These data suggest that improvement of glycemic control might prevent development of peripheral artery calcification in diabetic HD patients, and that GA provide better assay for glycemic control in that GA, in contrast to HbA1c, might be independent of erythropoietin injection in these patients. The influence of erythropoietin on HbA1C values was again evident by the data that the adjustment for the erythropoietin dose made the association of HbA1C with hand-artery calcification statistically significant even in patients with better glycemic control (Table 4). In our recent report, erythropoietin injection, in addition to casual PG, emerged as an independent factor associated with HbA1C in diabetic HD patients (Inaba et al., 2007). Increasing the erythropoietin dose causes a corresponding fall in hematocrit, and this has been shown to lower HbA1C even under the stable PG levels (Nakao et al., 1998). Since about 90% of diabetic HD patients receive erythropoietin in Japanese HD patients, the assessment of glycemic control using HbA1C gives a significant underestimation of glycemic control by an average of 33% (Inaba et al., 2007). Therefore, the HbA1C value may not be associated with hand-artery calcification due to its apparent modulation by erythropoietin, independently of glycemic control. Taking these data collectively, as glycemic control improves in diabetic HD patients, the rate of peripheral artery calcification might be reduced. Calcification of the hand arteries affects the medial layer and is of the type found in Moenckeberg's sclerosis (Edmonds, 2000; Cao et al., 2005). In contrast to the significant effect of calciumphosphate product on development of hand-artery calcification in non-diabetic HD patients, diabetic HD patients exhibit increased hand-artery calcification independently of the calcium-phosphate product (Ishimura et al., 2002). Increased hand-artery calcification seems to be associated with poor glycemic control, as reflected by the association with GA and HbA1C. Low bone turnover has also been associated with vascular calcification in diabetic HD patients (Galassi et al., 2006), and poor glycemic control induces low bone turnover by suppressing PTH secretion (Sugimoto et al., 1990), impairing osteoblast growth (Inaba et al., 1999), and reducing the responsiveness of osteoblasts to PTH (Inaba et al., 2002) and 1,25dihydroxyvitamin D3 (Inaba et al., 1999). A direct adverse effect of high glucose on vascular cells has also been proposed (Wadham et al., 2007; Srivastava et al., 2006). The mean values of monthly PG were essentially the same throughout the study period (data not shown), suggesting that glycemic control was stable during the preceding two months before determination of GA and HbA1C and that a single determination just
Table 4 Multiple regression analysis of factors independently associated with the presence of vascular calcification in 49 HD patients with diabetes Presence of vascular calcification
HD duration Erythropoietin dose Glycated albumin HbA1C R2
Model 1
Model 2
Model 3
Model 4
ß
P
ß
P
ß
p
ß
p
0.434
0.0011†
0.459
0.0007†
0.426 0.035
0.0019§ 0.7867
0.440 0.091
0.0014§ 0.5017
0.283
0.0283§
0.285
0.0290§
0.289†
0.245 0.0578⁎ 0.270†
0.290§
0.270 0.0465§ 0.277§
Values are standard regression coefficients (ß). R 2 = multiple coefficient of determination. †p b 0.001, §p b 0.05, ⁎p b 0.1. Presence of vascular calcification: (−) = 0, (+) = 1.
S. Yamada et al. / Life Sciences 83 (2008) 516–519
before the Monday/Tuesday hemodialysis session was representative of glycemic control in diabetic HD patients. HbA1C and GA reflect glycemic control over the preceding 4 to 6 weeks and 1 to 2 weeks (Tahara, 2000), respectively, and stable glycemic control during the preceding 2 months could negate the impact of acute changes assessed by HbA1C and GA in the present study, as previously described (Inaba et al., 2007). Glycated albumin acquires biological properties that are linked to the pathogenesis of diabetic vascular complications (Kennedy and Merimee, 1981; Cohen et al., 2006), suggesting that GA might contribute directly to vascular injury. As such, GA is better than HbA1C to associate with the development of vascular complications in diabetic HD patients. However, there is also a limitation to the GA assay, since albumin turnover is likely to change in patients who are maintained on peritoneal dialysis or have chronic renal failure with massive proteinuria. In such patients, GA values would theoretically be reduced due to shorter exposure to plasma albumin. Within this limitation, we suggest that GA provides a significantly better measure to reflect peripheral vascular calcification in diabetic HD patients, and that improvement of glycemic control might prevent development of vascular calcification in these patients. Conclusion The present study suggested that GA might be a better indicator of glycemic control in diabetic HD patients, and raise the possibility that improvement of glycemic control might prevent against the development of peripheral vascular calcification in those patients. References Cao, J.J., Hudson, M., Jankowski, M., Whitehouse, F., Weaver, W.D., 2005. Relation of chronic and acute glycemic control on mortality in acute myocardial infarction with diabetes mellitus. The American Journal of Cardiology 96 (2), 183–186. Cheung, A.K., Sarnak, M.J., Yan, G., Dwyer, J.T., Heyka, R.J., Rocco, M.V., Teehan, B.P., Levey, A.S., 2000. Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients. Kidney International 58 (1), 353–362. Cohen, M.P., Ziyadeh, F.N., Chen, S., 2006. Amadori-modified glycated serum proteins and accelerated atherosclerosis in diabetes: pathogenic and therapeutic implications. The Journal of Laboratory and Clinical Medicine 147 (5), 211–219. Cozzolino, M., Dusso, A.S., Slatopolsky, E., 2001. Role of calcium-phosphate product and bone-associated proteins on vascular calcification in renal failure. Journal of the American Society of Nephrology 12 (11), 2511–2516. Davies, M.R., Hruska, K.A., 2001. Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kidney International 60 (2), 472–479. Edmonds, M.E., 2000. Medial arterial calcification and diabetes mellitus. Zeitschrift fur Kardiologie 89 (2), 101–104. Galassi, A., Spiegel, D.M., Bellasi, A., Block, G.A., Raggi, P., 2006. Accelerated vascular calcification and relative hypoparathyroidism in incident haemodialysis diabetic patients receiving calcium binders. Nephrology, Dialysis, Transplantation 21 (11), 3215–3222. Goodman, W.G., Salusky, I.B., 2001. Non-invasive assessments of cardiovascular disease in patients with renal failure. Current Opinion in Nephrology and Hypertension 10 (3), 365–369. Inaba, M., Nishizawa, Y., Mita, K., Kumeda, Y., Emoto, M., Kawagishi, T., Ishimura, E., Nakatsuka, K., Shioi, A., Morii, H., 1999. Poor glycemic control impairs the response of biochemical parameters of bone formation and resorption to exogenous 1,25-dihydroxyvitamin D3 in patients with type 2 diabetes. Osteoporosis International 9 (6), 525–531. Inaba, M., Nagasue, K., Okuno, S., Ueda, M., Kumeda, Y., Imanishi, Y., Shoji, T., Ishimura, E., Ohta, T., Nakatani, T., Kim, M., Nishizawa, Y., 2002. Impaired secretion of
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