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Therapeutic Apheresis and Dialysis 2015; 19(1):40–44 doi: 10.1111/1744-9987.12204 © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Skin Autofluorescence Is a Predictor of Cardiovascular Disease in Chronic Kidney Disease Patients Fumihiko Furuya,1 Hiroki Shimura,2 Kazuya Takahashi,1 Daiichiro Akiyama,1 Ai Motosugi,3 Yukinobu Ikegishi,3 Kazutaka Haraguchi,3 and Tetsuro Kobayashi1 1
Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, 2Department of Laboratory Medicine, Fukushima Medical University, Fukushima and 3Haraguchi Internal Medicine-Kidney Clinic, Yamanashi, Japan
Abstract: Accelerated formation and tissue accumulation of advanced glycation end products (AGEs), reflecting cumulative glycemic and oxidative stress, occurs in agerelated and chronic diseases like diabetes mellitus (DM) and renal failure, and contributes to vascular damage. Skin autofluorescence (AFR), a noninvasive measurement method, reflects tissue accumulation of AGEs. AFR has been reported to be an independent predictor of mortality in Caucasian hemodialysis patients. We assessed the relationship between levels of AFR and the prevalence of cardiovascular disease (CVD), and clarified the prognostic usefulness of skin AFR levels in Asian (non-Caucasian) hemodialysis (HD) patients. AFR was measured with an autofluorescence reader in 64 HD patients. Overall and
cardiovascular mortality was monitored prospectively during the 3-year follow-up. During follow-up, CVD events occurred in 21 patients. The deaths of 10 HD patients were associated with CVD. Multivariate logistic regression analyses showed that initial AFR was an independent risk factor for de novo CVD in HD patients with or without diabetes. When patients were classified on the basis of AFR tertiles, Cochran-Armitage analysis demonstrated that the highest tertile of AFR level showed an increased odds ratio for the prevalence of CVD. These findings suggest that AFR levels can be used to detect the prevalence of CVD in HD patients with or without diabetes. Key Words: Coronary artery disease, Diabetes, Hemodialysis.
Chronic kidney disease (CKD) is an established risk factor for cardiovascular disease (CVD) (1). CVD is a major cause of death in Japanese individuals with CKD (2). However, concomitant conditions such as renal anemia cause subjects with CKD to have reduced tolerability to exercise, thereby masking the symptoms of CVDs. Extensive investigations into CVD for patients with CKD are not allowed, primarily because of socioeconomic reasons. A screening test is essential to detect CVD before considering specific studies for asymptomatic patients. The enhanced accumulation of tissue advanced glycation end products (AGEs) is the result of a
series of complex and sequential reactions.AGE accumulation results from a combination of hyperglycemia, oxidative/carbonyl stress, or decreased renal clearance of AGE precursors (2–4). Hyperglycemia is a sufficient but not necessary condition for increased abundance of AGE formation. AGE is significantly enhanced in uremia, even in the absence of hyperglycemia (5). Meerwaldt et al. reported a non-invasive optical tool, the autofluorescence reader, for assessing AGE accumulation in patients, based on skin autofluorescence (AFR) under ultraviolet light. They reported that AFR was correlated with collagen-linked fluorescence, pentosidine, and N-carboxymethyllysine accumulation in the skin, and long-term complications in patients with diabetes mellitus (DM), and that it was also a strong predictor of mortality in end stage renal disease (5,6). Because of its biochemical characteristics, AFR has been implicated as a contributing factor in the progression of chronic, age-related diseases, such as atherosclerosis and CVD (7,8).
Received March 2014; revised March 2014. Address correspondence and reprint requests to Dr Fumihiko Furuya Associate Professor, Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan. Email: [email protected]
40
Skin Autofluorescence in HD Patients The aim of this study was to investigate the association between CVD and AFR in Japanese (nonCaucasian) HD patients. PATIENTS AND METHODS The study protocol was approved by the Ethics Committees of the University of Yamanashi and Haraguchi Clinic (both in Yamanashi, Japan) in accordance with the Declaration of Helsinki (as revised in Edinburgh 2000). All patients provided written informed consent to participate in the study (#1094). Subjects This study was conducted on 64 chronic CKD patients undergoing 3- to 4-h sessions three times a week with standard bicarbonate HD. Blood samples were collected before a HD session on Monday or Tuesday. The following hematologic and biochemical tests were done using standard laboratory techniques: hemoglobin (Hb), albumin (Alb), low-density lipoprotein (LDL), triglycerides (TG), parathyroid hormone (PTH), C-reactive protein (CRP), and HbA1c. Levels of these parameters have been reported to be associated with CVD in CKD patients (9–11). Edema-free dry weight was determined for individual patients and the body mass index (BMI) was calculated. The ankle-brachial index (ABI), cardio-ankle vascular index (CAVI) and AFR were measured after a HD session because patients had stable dry weights (12). In the present study, CVD was defined as acute myocardial infarction, apoplexy, peripheral artery disease accompanied by toe necrosis, angina pectoris, or sudden cardiac death (13). Skin autofluorescence AGE accumulation was assessed based on the skin autofluorescence using the autofluorescence reader (AGE reader; DiagnOptics, Groningen, the Netherlands).The AFR illuminates a skin surface of approximately 1 cm2 at the lower arm, guarded against surrounding light, with an excitation light source between 300 and 420 nm. The amount of ultraviolet light exposure is small and the autofluorescence reader has already been tested in several studies without any adverse effect (5,6,14). Statistical analyses Data are case number or the means ± standard deviation (SD) in Tables. The Student’s t-test was applied to compare the mean values of variables. The frequency of de novo CVD during the 3-year follow-up across tertiles of AFR was represented as © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
41
the mean ±standard error (SE) and compared by Cochran–Armitage analyses. Logistic analyses were performed to evaluate the relationship between de novo CVD and AFR levels. Data were analyzed using JMP ver8 and SAS software (SAS Institute, San Francisco, CA, USA). RESULTS The demographic characteristics of the study group are summarized in Table 1. Seventy-three percent of the patients were male. The mean age of patients was 60.9 ± 13.2 years. The mean duration of HD was 4.79 ± 3.87 years. Fifty-six percent of the 64 patients had DM. Twenty-one patients experienced de novo CVD events during follow-up monitoring. The baseline characteristics of HD patients with and without de novo CVD after the 3-year follow-up are summarized in Table 2. Levels of HbA1c and AFR were significantly higher in patients with CVD than those without CVD (7.97 ± 0.72 vs. 6.14 ± 0.39% and 3.88 ± 0.18 vs. 3.19 ± 0.13, respectively, P < 0.05). The HD duration of de novo CVD patients was significantly longer than that in non-CVD patients. No significant differences were observed with respect to: gender, age, DM, serum Alb levels, LDL, TG, PTH, CRP, Hb and HbA1c. AFR did not correlate with HD duration and HbA1c (r = 0.05, P = 0.82 and r = 0.02, P = 0.53, respectively). Multivariate logistic regression analyses of the risk factors for de novo CVD were carried out (Table 3). TABLE 1. Patient background (N = 64) Male Age (years) HD duration (years) Diabetes Hypertension Dyslipidemia CAVI ABI Alb (g/dL) LDL (mg/dL) TG (mg/dL) PTH (pg/mL) CRP (mg/dL) Hb (g/dL) HbA1c (%) AFR
73.40% (N = 47) 60.90 ± 13.20 4.79 ± 3.87 56.30% (N = 36) 89.00% (N = 57) 10.90% (N = 7) 9.16 ± 1.53 1.09 ± 0.16 3.74 ± 0.49 93.40 ± 31.7 130.00 ± 86.3 167.00 ± 115 0.26 ± 0.34 11.00 ± 1.37 6.56 ± 1.44 3.40 ± 0.91
Values are numbers with percentages in parentheses or the mean ± SD. ABI, ankle–brachial index; AFR, skin autofluorescence; Alb, albumin; CAVI, cardio–ankle vascular index; CRP, C-reactive protein; Hb, hemoglobin; HbA1c, hemoglobin A1c; HD, hemdialysis; LDL, low-density lipoprotein; PTH, parathyroid hormone; TG, triglycerides.
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F Furuya et al. TABLE 2.
Baseline characteristics of hemodialysis (HD) patients according to 3-year follow-up monitoring
Male (%) Age (years) HD duration (years) Diabetes (%) Hypertension (%) Dyslipidemia Albumin (g/dL) LDL (mg/dL) TG (mg/dL) PTH (pg/mL) CRP (mg/dL) Hb (g/dL) HbA1c (%) AFR
No-CVD N = 43
de novo CVD N = 21
29 (67.4) 63.81 ± 2.10 3.94 ± 0.58 18 (41.9) 38 (88.4) 3 (6.9) 3.77 ± 0.08 90.41 ± 5.44 126.30 ± 15.14 164.82 ± 20.01 0.22 ± 0.07 11.17 ± 0.23 6.14 ± 0.39 3.19 ± 0.13
18 (85.7) 67.54 ± 3.12 6.52 ± 0.81 7 (33.3) 19 (90.5) 4 (19.1) 3.68 ± 0.13 100.79 ± 8.49 140.61 ± 24.12 175.00 ± 32.50 0.35 ± 0.11 10.63 ± 0.35 7.97 ± 0.72 3.88 ± 0.18
P 0.12 0.31 0.01>** 0.51 0.80 0.41 0.31 0.61 0.79 0.34 0.21 0.04* 0.01>**
Values are numbers with percentages in parentheses or the mean ± SD. *P < 0.05, **P < 0.01. CVD, cardiovascular disease.
Gender, age, duration of HD, DM, hypertension, dyslipidemia, Alb, LDL, TG, PTH, CRP, Hb, HbA1c, and AFR were used as independent variables, and de novo CVD as the dependent variable. Univariate analyses in all subjects showed that the prevalence of de novo CVD correlated with HD duration and AFR level (P < 0.01). Multivariate logistic regression analyses of risk factors showed that the prevalence of de novo CVD in HD patients was independently associated with HD duration and AFR. Patients in the upper tertile of AFR level had a significantly higher prevalence of CVD (P < 0.01
for trend) (Fig. 1). These results suggested that high levels of AFR were useful predictors of CVD in HD patients.
DISCUSSION AND CONCLUSION In the present study, AFR levels were significantly higher in HD patients with de novo CVD than in those without de novo CVD. The initial AFR value was significantly associated with the prevalence of CVD. The association between enhanced AFR levels
TABLE 3. Multiple logistic analyses for cardiovascular disease (CVD) in hemodialysis (HD) patients according to clinical characteristics and parameters in univariate and multivariate models Univariate model
Male Age HD duration Diabetes Hypertension Dyslipidemia Albumin LDL TG PTH CRP Hb HbA1c AFR
Multivariate model
OR
95% CI
P
2.89 1.02 1.25 0.18 0.11 0.57 0.63 1.01 1.00 1.00 1.00 0.75 1.09 2.70
0.81–13.82 0.98–1.06 1.04–1.72 −0.35–0.75 −0.71–1.11 −0.23–1.43 0.13–2.27 0.99–1.03 0.99–1.01 0.99–1.01 0.99–1.01 0.47–1.17 0.57–2.15 1.31–6.78
0.11 0.31 0.01>** 0.51 0.80 0.17 0.15 0.06 0.62 0.79 0.62 0.20 0.09 0.01>**
OR
95% CI
P
1.34
1.05–2.08
0.01>**
2.96
1.26–8.16
0.01>**
AFR, autofluorescence; CI, confidence interval; CRP, C-reactive protein; Hb, hemoglobin; LDL, low-density lipoprotein; OR, odds ratio; PTH, parathyroid hormone; TG, triglycerides. **P < 0.01.
Ther Apher Dial, Vol. 19, No. 1, 2015
© 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Skin Autofluorescence in HD Patients
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clinical usefulness of the measurement of AFR levels. Further research is needed to confirm the role of skin autofluorescence levels in the pathogenesis and progression of cardiovascular disease in patients with hemodialysis. Acknowledgments: We thank the staff of the Haraguchi Internal Medicine-Kidney Clinic for their efforts in the measurement of AFR, CAVI and ABI. The present study received no financial support. Conflict of interest: There was no conflict of interest that could be perceived as prejudicing the impartiality of the research reported here. FIG. 1. Prevalence of cardiovascular disease (CVD) according to autofluorescence (AFR) tertiles. Values are numbers with percentages or the mean ± standard error (SE). CVD, cardiovascular disease; T, tertile; T1: AFR3.65 * P < 0.01 for trend.
and an increased prevalence of CVD remained independent of age, sex and DM. Consistent with other reports, de novo CVD in HD patients (Caucasian) was also associated with the initial value of AFR (5). Recent reports also indicated that AGE inhibitors and angiotensin receptor blockers inhibit AGE formation in animal models of diabetes, further implicating AGE as a biomarker or causative factor in the development of diabetic nephropathy. Investigation of the influence of tissue AGE accumulation is an invasive, expensive procedure, and blood or urine sampling of AGE does not necessarily reflect tissue AGE (15). However, tissue AFR has been related to the accumulation of AGE and to the progression of chronic complications of DM and the end stage of renal disease (ESRD) (16). The present study is the first to report that the AFR value of HD patients is a significant independent risk factor for de novo CVD according to multivariate logistic analyses. Cardiovascular disease has become the leading cause of death in HD patients (2). Understanding the mechanisms involved in the development of CVD and identification of biomarkers are important steps in reducing cardiovascular mortality in patients with CKD or HD patients. The present study suggests that AFR values may play an important role in the diagnosis and detection of CVD in HD patients. Our study supports the importance of AFR enhancement in the pathogenesis of vascular disease. Non-invasive measurement of AFR could become a rapid tool for risk assessment and provide a novel approach for monitoring the role of AFR in disease. However, the present study had one limitation: there were insufficient numbers of subjects to clearly demonstrate the © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
REFERENCES 1. Sarnak MJ, Levey AS, Schoolwerth AC et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003;108:2154–69. 2. Nakamura K, Okamura T, Hayakawa T et al. Chronic kidney disease is a risk factor for cardiovascular death in a community-based population in Japan: NIPPON DATA90. Circ J 2006;70:954–9. 3. Locatelli F, Canaud B, Eckardt KU, Stenvinkel P, Wanner C, Zoccali C. The importance of diabetic nephropathy in current nephrological practice. Nephrol Dial Transplant 2003;18:1716– 25. 4. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999;48:1–9. 5. Meerwaldt R, Hartog JW, Graaff R et al. Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, predicts mortality in hemodialysis patients. J Am Soc Nephrol 2005;16:3687–93. 6. Meerwaldt R, Graaff R, Oomen PH et al. Simple non-invasive assessment of advanced glycation endproduct accumulation. Diabetologia 2004;47:1324–30. 7. Aronson D. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens 2003;21:3–12. 8. Yan SF, Ramasamy R, Naka Y, Schmidt AM. Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond. Circ Res 2003;93:1159– 69. 9. Suzuki M, Hada Y, Akaishi M et al. Effects of anemia correction by erythropoiesis-stimulating agents on cardiovascular function in non-dialysis patients with chronic kidney disease. Int Heart J 2012;53:238–43. 10. Hsu HJ, Yen CH, Chen CK et al. Low plasma DHEA-S increases mortality risk among male hemodialysis patients. Exp Gerontol 2012;47:950–7. 11. Morishita Y, Hanawa S, Chinda J, Iimura O, Tsunematsu S, Kusano E. Effects of aliskiren on blood pressure and the predictive biomarkers for cardiovascular disease in hemodialysisdependent chronic kidney disease patients with hypertension. Hypertens Res 2011;34:308–13. 12. Takenaka T, Hoshi H, Kato N et al. Cardio-ankle vascular index to screen cardiovascular diseases in patients with endstage renal diseases. J Atheroscler Thromb 2008;15:339–44. 13. Terawaki H, Nakayama M, Miyazawa E et al. Effect of allopurinol on cardiovascular incidence among hypertensive nephropathy patients: the Gonryo study. Clin Exp Nephrol 2013;17:549–53.
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14. Tanaka K, Katoh T, Asai J et al. Relationship of skin autofluorescence to cardiovascular disease in Japanese hemodialysis patients. Ther Apher Dial 2009;14:334– 40. 15. Hricik DE, Wu YC, Schulak A, Friedlander MA. Disparate changes in plasma and tissue pentosidine levels after
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kidney and kidney-pancreas transplantation. Clin Transplant 1996;10(6 Pt 1):568–73. 16. Monnier VM, Vishwanath V, Frank KE, Elmets CA, Dauchot P, Kohn RR. Relation between complications of type I diabetes mellitus and collagen-linked fluorescence. N Engl J Med 1986;314:403–8.
© 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Therapeutic Apheresis and Dialysis 2015; 19(1):40–44 doi: 10.1111/1744-9987.12204 © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Skin Autofluorescence Is a Predictor of Cardiovascular Disease in Chronic Kidney Disease Patients Fumihiko Furuya,1 Hiroki Shimura,2 Kazuya Takahashi,1 Daiichiro Akiyama,1 Ai Motosugi,3 Yukinobu Ikegishi,3 Kazutaka Haraguchi,3 and Tetsuro Kobayashi1 1
Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, 2Department of Laboratory Medicine, Fukushima Medical University, Fukushima and 3Haraguchi Internal Medicine-Kidney Clinic, Yamanashi, Japan
Abstract: Accelerated formation and tissue accumulation of advanced glycation end products (AGEs), reflecting cumulative glycemic and oxidative stress, occurs in agerelated and chronic diseases like diabetes mellitus (DM) and renal failure, and contributes to vascular damage. Skin autofluorescence (AFR), a noninvasive measurement method, reflects tissue accumulation of AGEs. AFR has been reported to be an independent predictor of mortality in Caucasian hemodialysis patients. We assessed the relationship between levels of AFR and the prevalence of cardiovascular disease (CVD), and clarified the prognostic usefulness of skin AFR levels in Asian (non-Caucasian) hemodialysis (HD) patients. AFR was measured with an autofluorescence reader in 64 HD patients. Overall and
cardiovascular mortality was monitored prospectively during the 3-year follow-up. During follow-up, CVD events occurred in 21 patients. The deaths of 10 HD patients were associated with CVD. Multivariate logistic regression analyses showed that initial AFR was an independent risk factor for de novo CVD in HD patients with or without diabetes. When patients were classified on the basis of AFR tertiles, Cochran-Armitage analysis demonstrated that the highest tertile of AFR level showed an increased odds ratio for the prevalence of CVD. These findings suggest that AFR levels can be used to detect the prevalence of CVD in HD patients with or without diabetes. Key Words: Coronary artery disease, Diabetes, Hemodialysis.
Chronic kidney disease (CKD) is an established risk factor for cardiovascular disease (CVD) (1). CVD is a major cause of death in Japanese individuals with CKD (2). However, concomitant conditions such as renal anemia cause subjects with CKD to have reduced tolerability to exercise, thereby masking the symptoms of CVDs. Extensive investigations into CVD for patients with CKD are not allowed, primarily because of socioeconomic reasons. A screening test is essential to detect CVD before considering specific studies for asymptomatic patients. The enhanced accumulation of tissue advanced glycation end products (AGEs) is the result of a
series of complex and sequential reactions.AGE accumulation results from a combination of hyperglycemia, oxidative/carbonyl stress, or decreased renal clearance of AGE precursors (2–4). Hyperglycemia is a sufficient but not necessary condition for increased abundance of AGE formation. AGE is significantly enhanced in uremia, even in the absence of hyperglycemia (5). Meerwaldt et al. reported a non-invasive optical tool, the autofluorescence reader, for assessing AGE accumulation in patients, based on skin autofluorescence (AFR) under ultraviolet light. They reported that AFR was correlated with collagen-linked fluorescence, pentosidine, and N-carboxymethyllysine accumulation in the skin, and long-term complications in patients with diabetes mellitus (DM), and that it was also a strong predictor of mortality in end stage renal disease (5,6). Because of its biochemical characteristics, AFR has been implicated as a contributing factor in the progression of chronic, age-related diseases, such as atherosclerosis and CVD (7,8).
Received March 2014; revised March 2014. Address correspondence and reprint requests to Dr Fumihiko Furuya Associate Professor, Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan. Email: [email protected]
40
Skin Autofluorescence in HD Patients The aim of this study was to investigate the association between CVD and AFR in Japanese (nonCaucasian) HD patients. PATIENTS AND METHODS The study protocol was approved by the Ethics Committees of the University of Yamanashi and Haraguchi Clinic (both in Yamanashi, Japan) in accordance with the Declaration of Helsinki (as revised in Edinburgh 2000). All patients provided written informed consent to participate in the study (#1094). Subjects This study was conducted on 64 chronic CKD patients undergoing 3- to 4-h sessions three times a week with standard bicarbonate HD. Blood samples were collected before a HD session on Monday or Tuesday. The following hematologic and biochemical tests were done using standard laboratory techniques: hemoglobin (Hb), albumin (Alb), low-density lipoprotein (LDL), triglycerides (TG), parathyroid hormone (PTH), C-reactive protein (CRP), and HbA1c. Levels of these parameters have been reported to be associated with CVD in CKD patients (9–11). Edema-free dry weight was determined for individual patients and the body mass index (BMI) was calculated. The ankle-brachial index (ABI), cardio-ankle vascular index (CAVI) and AFR were measured after a HD session because patients had stable dry weights (12). In the present study, CVD was defined as acute myocardial infarction, apoplexy, peripheral artery disease accompanied by toe necrosis, angina pectoris, or sudden cardiac death (13). Skin autofluorescence AGE accumulation was assessed based on the skin autofluorescence using the autofluorescence reader (AGE reader; DiagnOptics, Groningen, the Netherlands).The AFR illuminates a skin surface of approximately 1 cm2 at the lower arm, guarded against surrounding light, with an excitation light source between 300 and 420 nm. The amount of ultraviolet light exposure is small and the autofluorescence reader has already been tested in several studies without any adverse effect (5,6,14). Statistical analyses Data are case number or the means ± standard deviation (SD) in Tables. The Student’s t-test was applied to compare the mean values of variables. The frequency of de novo CVD during the 3-year follow-up across tertiles of AFR was represented as © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
41
the mean ±standard error (SE) and compared by Cochran–Armitage analyses. Logistic analyses were performed to evaluate the relationship between de novo CVD and AFR levels. Data were analyzed using JMP ver8 and SAS software (SAS Institute, San Francisco, CA, USA). RESULTS The demographic characteristics of the study group are summarized in Table 1. Seventy-three percent of the patients were male. The mean age of patients was 60.9 ± 13.2 years. The mean duration of HD was 4.79 ± 3.87 years. Fifty-six percent of the 64 patients had DM. Twenty-one patients experienced de novo CVD events during follow-up monitoring. The baseline characteristics of HD patients with and without de novo CVD after the 3-year follow-up are summarized in Table 2. Levels of HbA1c and AFR were significantly higher in patients with CVD than those without CVD (7.97 ± 0.72 vs. 6.14 ± 0.39% and 3.88 ± 0.18 vs. 3.19 ± 0.13, respectively, P < 0.05). The HD duration of de novo CVD patients was significantly longer than that in non-CVD patients. No significant differences were observed with respect to: gender, age, DM, serum Alb levels, LDL, TG, PTH, CRP, Hb and HbA1c. AFR did not correlate with HD duration and HbA1c (r = 0.05, P = 0.82 and r = 0.02, P = 0.53, respectively). Multivariate logistic regression analyses of the risk factors for de novo CVD were carried out (Table 3). TABLE 1. Patient background (N = 64) Male Age (years) HD duration (years) Diabetes Hypertension Dyslipidemia CAVI ABI Alb (g/dL) LDL (mg/dL) TG (mg/dL) PTH (pg/mL) CRP (mg/dL) Hb (g/dL) HbA1c (%) AFR
73.40% (N = 47) 60.90 ± 13.20 4.79 ± 3.87 56.30% (N = 36) 89.00% (N = 57) 10.90% (N = 7) 9.16 ± 1.53 1.09 ± 0.16 3.74 ± 0.49 93.40 ± 31.7 130.00 ± 86.3 167.00 ± 115 0.26 ± 0.34 11.00 ± 1.37 6.56 ± 1.44 3.40 ± 0.91
Values are numbers with percentages in parentheses or the mean ± SD. ABI, ankle–brachial index; AFR, skin autofluorescence; Alb, albumin; CAVI, cardio–ankle vascular index; CRP, C-reactive protein; Hb, hemoglobin; HbA1c, hemoglobin A1c; HD, hemdialysis; LDL, low-density lipoprotein; PTH, parathyroid hormone; TG, triglycerides.
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F Furuya et al. TABLE 2.
Baseline characteristics of hemodialysis (HD) patients according to 3-year follow-up monitoring
Male (%) Age (years) HD duration (years) Diabetes (%) Hypertension (%) Dyslipidemia Albumin (g/dL) LDL (mg/dL) TG (mg/dL) PTH (pg/mL) CRP (mg/dL) Hb (g/dL) HbA1c (%) AFR
No-CVD N = 43
de novo CVD N = 21
29 (67.4) 63.81 ± 2.10 3.94 ± 0.58 18 (41.9) 38 (88.4) 3 (6.9) 3.77 ± 0.08 90.41 ± 5.44 126.30 ± 15.14 164.82 ± 20.01 0.22 ± 0.07 11.17 ± 0.23 6.14 ± 0.39 3.19 ± 0.13
18 (85.7) 67.54 ± 3.12 6.52 ± 0.81 7 (33.3) 19 (90.5) 4 (19.1) 3.68 ± 0.13 100.79 ± 8.49 140.61 ± 24.12 175.00 ± 32.50 0.35 ± 0.11 10.63 ± 0.35 7.97 ± 0.72 3.88 ± 0.18
P 0.12 0.31 0.01>** 0.51 0.80 0.41 0.31 0.61 0.79 0.34 0.21 0.04* 0.01>**
Values are numbers with percentages in parentheses or the mean ± SD. *P < 0.05, **P < 0.01. CVD, cardiovascular disease.
Gender, age, duration of HD, DM, hypertension, dyslipidemia, Alb, LDL, TG, PTH, CRP, Hb, HbA1c, and AFR were used as independent variables, and de novo CVD as the dependent variable. Univariate analyses in all subjects showed that the prevalence of de novo CVD correlated with HD duration and AFR level (P < 0.01). Multivariate logistic regression analyses of risk factors showed that the prevalence of de novo CVD in HD patients was independently associated with HD duration and AFR. Patients in the upper tertile of AFR level had a significantly higher prevalence of CVD (P < 0.01
for trend) (Fig. 1). These results suggested that high levels of AFR were useful predictors of CVD in HD patients.
DISCUSSION AND CONCLUSION In the present study, AFR levels were significantly higher in HD patients with de novo CVD than in those without de novo CVD. The initial AFR value was significantly associated with the prevalence of CVD. The association between enhanced AFR levels
TABLE 3. Multiple logistic analyses for cardiovascular disease (CVD) in hemodialysis (HD) patients according to clinical characteristics and parameters in univariate and multivariate models Univariate model
Male Age HD duration Diabetes Hypertension Dyslipidemia Albumin LDL TG PTH CRP Hb HbA1c AFR
Multivariate model
OR
95% CI
P
2.89 1.02 1.25 0.18 0.11 0.57 0.63 1.01 1.00 1.00 1.00 0.75 1.09 2.70
0.81–13.82 0.98–1.06 1.04–1.72 −0.35–0.75 −0.71–1.11 −0.23–1.43 0.13–2.27 0.99–1.03 0.99–1.01 0.99–1.01 0.99–1.01 0.47–1.17 0.57–2.15 1.31–6.78
0.11 0.31 0.01>** 0.51 0.80 0.17 0.15 0.06 0.62 0.79 0.62 0.20 0.09 0.01>**
OR
95% CI
P
1.34
1.05–2.08
0.01>**
2.96
1.26–8.16
0.01>**
AFR, autofluorescence; CI, confidence interval; CRP, C-reactive protein; Hb, hemoglobin; LDL, low-density lipoprotein; OR, odds ratio; PTH, parathyroid hormone; TG, triglycerides. **P < 0.01.
Ther Apher Dial, Vol. 19, No. 1, 2015
© 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Skin Autofluorescence in HD Patients
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clinical usefulness of the measurement of AFR levels. Further research is needed to confirm the role of skin autofluorescence levels in the pathogenesis and progression of cardiovascular disease in patients with hemodialysis. Acknowledgments: We thank the staff of the Haraguchi Internal Medicine-Kidney Clinic for their efforts in the measurement of AFR, CAVI and ABI. The present study received no financial support. Conflict of interest: There was no conflict of interest that could be perceived as prejudicing the impartiality of the research reported here. FIG. 1. Prevalence of cardiovascular disease (CVD) according to autofluorescence (AFR) tertiles. Values are numbers with percentages or the mean ± standard error (SE). CVD, cardiovascular disease; T, tertile; T1: AFR3.65 * P < 0.01 for trend.
and an increased prevalence of CVD remained independent of age, sex and DM. Consistent with other reports, de novo CVD in HD patients (Caucasian) was also associated with the initial value of AFR (5). Recent reports also indicated that AGE inhibitors and angiotensin receptor blockers inhibit AGE formation in animal models of diabetes, further implicating AGE as a biomarker or causative factor in the development of diabetic nephropathy. Investigation of the influence of tissue AGE accumulation is an invasive, expensive procedure, and blood or urine sampling of AGE does not necessarily reflect tissue AGE (15). However, tissue AFR has been related to the accumulation of AGE and to the progression of chronic complications of DM and the end stage of renal disease (ESRD) (16). The present study is the first to report that the AFR value of HD patients is a significant independent risk factor for de novo CVD according to multivariate logistic analyses. Cardiovascular disease has become the leading cause of death in HD patients (2). Understanding the mechanisms involved in the development of CVD and identification of biomarkers are important steps in reducing cardiovascular mortality in patients with CKD or HD patients. The present study suggests that AFR values may play an important role in the diagnosis and detection of CVD in HD patients. Our study supports the importance of AFR enhancement in the pathogenesis of vascular disease. Non-invasive measurement of AFR could become a rapid tool for risk assessment and provide a novel approach for monitoring the role of AFR in disease. However, the present study had one limitation: there were insufficient numbers of subjects to clearly demonstrate the © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
REFERENCES 1. Sarnak MJ, Levey AS, Schoolwerth AC et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003;108:2154–69. 2. Nakamura K, Okamura T, Hayakawa T et al. Chronic kidney disease is a risk factor for cardiovascular death in a community-based population in Japan: NIPPON DATA90. Circ J 2006;70:954–9. 3. Locatelli F, Canaud B, Eckardt KU, Stenvinkel P, Wanner C, Zoccali C. The importance of diabetic nephropathy in current nephrological practice. Nephrol Dial Transplant 2003;18:1716– 25. 4. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999;48:1–9. 5. Meerwaldt R, Hartog JW, Graaff R et al. Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, predicts mortality in hemodialysis patients. J Am Soc Nephrol 2005;16:3687–93. 6. Meerwaldt R, Graaff R, Oomen PH et al. Simple non-invasive assessment of advanced glycation endproduct accumulation. Diabetologia 2004;47:1324–30. 7. Aronson D. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens 2003;21:3–12. 8. Yan SF, Ramasamy R, Naka Y, Schmidt AM. Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond. Circ Res 2003;93:1159– 69. 9. Suzuki M, Hada Y, Akaishi M et al. Effects of anemia correction by erythropoiesis-stimulating agents on cardiovascular function in non-dialysis patients with chronic kidney disease. Int Heart J 2012;53:238–43. 10. Hsu HJ, Yen CH, Chen CK et al. Low plasma DHEA-S increases mortality risk among male hemodialysis patients. Exp Gerontol 2012;47:950–7. 11. Morishita Y, Hanawa S, Chinda J, Iimura O, Tsunematsu S, Kusano E. Effects of aliskiren on blood pressure and the predictive biomarkers for cardiovascular disease in hemodialysisdependent chronic kidney disease patients with hypertension. Hypertens Res 2011;34:308–13. 12. Takenaka T, Hoshi H, Kato N et al. Cardio-ankle vascular index to screen cardiovascular diseases in patients with endstage renal diseases. J Atheroscler Thromb 2008;15:339–44. 13. Terawaki H, Nakayama M, Miyazawa E et al. Effect of allopurinol on cardiovascular incidence among hypertensive nephropathy patients: the Gonryo study. Clin Exp Nephrol 2013;17:549–53.
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14. Tanaka K, Katoh T, Asai J et al. Relationship of skin autofluorescence to cardiovascular disease in Japanese hemodialysis patients. Ther Apher Dial 2009;14:334– 40. 15. Hricik DE, Wu YC, Schulak A, Friedlander MA. Disparate changes in plasma and tissue pentosidine levels after
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kidney and kidney-pancreas transplantation. Clin Transplant 1996;10(6 Pt 1):568–73. 16. Monnier VM, Vishwanath V, Frank KE, Elmets CA, Dauchot P, Kohn RR. Relation between complications of type I diabetes mellitus and collagen-linked fluorescence. N Engl J Med 1986;314:403–8.
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