Clin Exp Nephrol (2012) 16:629–635 DOI 10.1007/s10157-012-0610-x
ORIGINAL ARTICLE
A lower level of reduced albumin induces serious cardiovascular incidence among peritoneal dialysis patients Hiroyuki Terawaki • Yukie Matsuyama • Nanae Matsuo • Makoto Ogura Jun Mitome • Akihiko Hamaguchi • Tomoyoshi Terada • Seiichi Era • Tatsuo Hosoya
•
Received: 16 October 2011 / Accepted: 30 January 2012 / Published online: 23 February 2012 Ó Japanese Society of Nephrology 2012
Abstract Background Human serum albumin is composed of human mercaptoalbumin (HMA) with cysteine residues having reducing powers and of oxidized human non-mercaptoalbumin. Previously, we reported that a lower HMA level is closely related to serious cardiovascular disease (CVD) incidence and mortality among hemodialysis patients. However, the relationship between HMA level and CVD incidence among peritoneal dialysis (PD) patients is unclear. Methods We measured the redox state of human serum albumin using high-performance liquid chromatography in 30 continuous ambulatory PD patients. The association between HMA and incidental CVD events was evaluated. Results Eight patients experienced symptomatic CVD events (5 patients died) at the 5-year follow-up. The concentration and fraction of HMA (cHMA and f(HMA), respectively) showed significantly lower values in patients with CVD than those without CVD (cHMA 1.58 ± 0.39 and 2.16 ± 0.43 g/dL, f(HMA) 48.9 ± 5.4 and 56.4 ± 8.6%, respectively). Multiple forward stepwise regression analysis using cHMA and f(HMA) as the criterion variables H. Terawaki N. Matsuo M. Ogura J. Mitome A. Hamaguchi T. Hosoya Division of Kidney and Hypertension, The Jikei University School of Medicine, Tokyo, Japan H. Terawaki (&) Division of Kidney and Hypertension, The Jikei University Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba 277-8567, Japan e-mail:
[email protected] Y. Matsuyama T. Terada S. Era Division of Physiology and Biophysics, Gifu University Graduate School of Medicine, Gifu, Japan
was performed, and C-reactive protein and hemoglobin were adopted as significant explanatory variables in the former equation, whereas urea nitrogen was adopted in the latter equation. Multiple logistic regression analysis revealed that cHMA is a statistically, and f(HMA) is a marginally significant explanatory variable of CVD incidence (p = 0.0369, R = -0.260 and p = 0.0580, R = -0.214, respectively). Conclusions Lower HMA level, which might be caused by chronic inflammation, anemia and accumulation of dialyzable uremic toxin(s), is closely related to serious CVD incidence among PD patients. Keywords Cardiovascular disease Peritoneal dialysis Oxidative stress Redox state of albumin
Introduction Mortality among end-stage renal disease (ESRD) patients is higher than among the general population. In Japan, the mortality rate of ESRD patients on regular renal replacement therapy is twice as high as that of the general population. The leading cause of mortality among ESRD patients is cardiovascular disease (CVD) such as heart failure, apoplexy, myocardial infarction and peripheral artery disease [1]. If the incidence of CVD among ESRD could be suppressed, then the prognosis for ESRD patients could be improved. However, the effective strategy to suppress CVD is not clear, because the reason why CVD is so common among ESRD patients is fully understood. Recently, we found that a lower serum level of reduced albumin strongly contributes to CVD incidence among ESRD patients on regular hemodialysis (HD) therapy [2].
123
630
From the view point of the redox state of free cysteine residue at position 34 from the N-terminus, human serum albumin (HSA) is a mixture of human mercaptoalbumin (HMA) in which the mercapto group is reduced, human non-mercaptoalbumin (HNA-1) which is the disulfide bond formation reversibly oxidized by either cysteine or glutathion, and HNA-2 which is strongly oxidized and becomes sulfinic or sulfonic. Because approximately 80% of the total free thiol content in plasma is made up by the thiol group of albumin [3], it is thought that a decrease of reduced albumin or HMA could induce serious complications via insufficient reductive capacity. The aim of the present study is to prove that the lower serum level of reduced albumin (HMA) is a powerful independent risk factor for serious CVD incidence among ESRD patients on peritoneal dialysis (PD), in a similar way as patients on HD. We performed measurements of the redox state of HSA in 30 ESRD patients on PD, and compared them with incidence and mortality due to CVD. As a result, our study revealed a close relationship between the lower serum level of reduced albumin (HMA) and serious CVD incidence.
Methods The present study is a prospective, single center cohort study of 5 years follow-up. The study involved 30 PD patients— 15 males and 15 females aged between 39 and 86 (62 ± 12) years who attended the Jikei University Kashiwa Hospital. All patients were on standard continuous ambulatory PD (three to five times exchange daily) using acid/high-glucose degradation product (GDP) solutions or neutral/lowGDP glucose solutions as peritoneal dialysate (n = 12 and 18, respectively). Patients with apparent infection, bleeding, liver dysfunction, collagen disease, systemic vasculitis, or malignancies were not included in this study. Patients with a history of apparent myocardial infarction or stroke were also excluded. No patient had received antioxidant agents such as ascoribic acid or vitamin E. Local committee approved the study protocol and written informed consent was obtained from all participants. Blood samples for measurement of HSA (Cys-34)-redox were obtained: 2 mL was drawn from the serum obtained by centrifugation, and stored at -80°C until analysis. In addition, the following hematologic and biochemical tests were performed using standard laboratory techniques: hemoglobin, total protein, albumin, urea nitrogen, creatinine, uric acid, sodium, potassium, chloride, calcium, inorganic phosphorus, magnesium, transferrin saturation, b2-microglubulin, and C-reactive protein (CRP). Measurement of the albumin redox state was performed using the high-performance liquid chromatography
123
Clin Exp Nephrol (2012) 16:629–635
(HPLC) method reported previously [4]. The HPLC system consisted of an AS-8010 autosampler (injection volume 2 lL specimen; Tosoh, Tokyo, Japan) and a CCPM double-plunger pump (Tosoh) in conjunction with a SC-8020 system controller (Tosoh). The chromatograph was obtained using a Finnigan UV6000LP photo diode alley detector (detection area 200–600 nm with 1-nm step; Thermo Electron, Waltham, MA, USA). A Shodex-Asahipak ES-502N 7C column [10 9 0.76 cm (inner diameter), dimethylaminoethyl-form for ion-exchange HPLC, column temperature 35 ± 0.5°C; Showa Denko, Tokyo, Japan] was used in this study. Elution was performed by linear gradient elution with ethanol concentrations (0–1 min, 0%; 1–50 min, 0 ? 10%; 50–55 min, 10 ? 0%; 55–60 min, 0%) for specimen in 0.05 M sodium acetate and 0.40 M sodium sulfate mixture (pH 4.85) at a flow rate of 1.0 mL/ min. Deaeration of the buffer solution was performed by bubbling helium. HPLC profiles obtained from these procedures were subjected to numerical curve-fitting using simulation software (PeakFit version 4.05; SPSS Science, Chicago, IL, USA), and each peak shape was approximated by a Gaussian function. From HPLC profiles of HSA obtained from these procedures, the value for each fraction of HMA, HNA-1, and HNA-2 to total HSA [f(HMA), f(HNA-1), f(HNA-2)] were calculated. Using these values and albumin concentration, the concentration for each fraction (cHMA, cHNA-1 and cHNA-2) were also calculated. Five years after the measurement of HSA-redox, the vital and CVD status of participants were established, and the relationship between CVD and HSA-redox was evaluated. In this study, CVD was defined as (1) acute myocardial infarction, (2) apoplexy, (3) peripheral artery disease accompanied with toe necrosis, or (4) sudden cardiac death (sudden death without signs of any other diseases such as apoplexy, gastrointestinal bleeding, acute infection or malignancies). We used the statistical software Stat View 5.0 (SAS Institute, Inc., Cary, NC, USA). Data are presented as mean ± SD, unless otherwise specified. Values were compared by unpaired t test or Chi-squared test, as appropriate. For the magnitude of the correlation, we used Pearson’s correlation coefficient (R). For all analyses, twotailed p \ 0.05 was considered statistically significant. The authors had full access to the data and take responsibility for its integrity.
Results A total of 8 patients experienced symptomatic CVD events at the 5-year follow-up—cerebral infarction (n = 5), peripheral artery disease (n = 2) or acute myocardial
Clin Exp Nephrol (2012) 16:629–635
631
Table 1 Characteristics of respective groups
* p \ 0.05 versus CVD (-) group
CVD (?) (n = 8)
p value
Age (years)
59.7 ± 11.4
69.4 ± 11.6
0.0512
Gender (%male)
59.1
25.0
0.0986
Dialysis vintage (months)
41.4 ± 20.0
37.3 ± 17.4
0.6117
Primary disease (%diabetes)
13.6
50.0
0.0373*
Combination of weekly HD (%)
27.3
12.5
0.4171
Oliguric patients (%)
54.5
75.0
0.3287
Usage of acid/high-GDP solutions (%)
27.3
75.0
0.0183*
CVD (?) (n = 8)
p value
Table 2 Laboratory data of respective groups
CVD (-) (n = 22) Hemoglobin (g/dL)
9.86 ± 1.96
9.18 ± 1.05
0.3620
Alanine aminotransferase (IU/L)
13.9 ± 7.5
11.3 ± 5.8
0.3829
Total protein (g/dL)
6.49 ± 0.43
6.38 ± 0.91
0.6386
Urea nitrogen (mg/dL)
60.1 ± 16.1
57.8 ± 9.8
0.6986
Creatinine (mg/dL)
10.93 ± 2.88
8.89 ± 3.61
0.1195
Uric acid (mg/dL)
7.51 ± 1.56
7.24 ± 1.18
0.6586
Sodium (mEq/L) Potassium (mEq/L)
* p \ 0.05 versus CVD (-) group
CVD (-) (n = 22)
141.9 ± 3.2 4.47 ± 0.65
142.6 ± 4.5 4.01 ± 0.75
0.6332 0.1116
Chloride (mEq/L)
99.7 ± 4.4
99.9 ± 2.9
0.9091
Corrected calcium (mg/dL)
9.56 ± 0.65
9.38 ± 0.57
0.4761
Inorganic phosphorus (mg/dL) Magnesium (mg/dL)
5.40 ± 1.11 2.29 ± 0.41
6.11 ± 1.26 2.25 ± 0.64
0.1414 0.8373
b2-microglobulin (lg/dL)
30.96 ± 10.70
34.85 ± 11.76
0.3983
Transferrin saturation (%)
33.4 ± 15.0
21.7 ± 6.9
0.0445*
C-reactive protein (mg/dL)
0.20 ± 0.17
0.50 ± 0.65
0.0470*
infarction (n = 1). Among these patients, 5 subjects died within 1 month after the CVD event. Patients were then stratified into two groups—CVD (-) group (n = 22) or CVD (?) group (n = 8). Basic characteristics and laboratory data of the respective groups at the beginning of this study are shown in Tables 1 and 2, respectively. In the CVD (?) group, the percentage of diabetes, usage of acid/high-GDP solutions, and CRP were significantly higher, whereas transferrin saturation was significantly lower. Serum albumin and its redox state at the beginning of this study are shown in Table 3. With regard to the the redox state of HSA (Cys-34), the concentration of HMA (cHMA) was significantly lower in the CVD (?) group than in the CVD (-) group (1.58 ± 0.39 and 2.16 ± 0.43 g/dL, respectively, p = 0.0026), and the ratio of HMA (f(HMA)) was also significantly lower in the CVD (?) group than in the CVD (-) group (48.9 ± 5.4 and 56.4 ± 8.6%, respectively, p = 0.0278). With regard to the value of HNA-1, the ratio (f(HNA-1)) was significantly higher in
the CVD (?) group than in the CVD (-) group (40.5 ± 8.1 and 47.6 ± 5.2%, respectively, p = 0.0282), whereas such a difference was not observed in the comparison between concentration (cHNA-1) in the CVD (?) group and that in the CVD (-) group (1.52 ± 0.31 and 1.53 ± 0.29 g/dL, respectively, p = 0.9152). With regard to the value of HNA-2, neither the concentration (cHNA-2 0.12 ± 0.02 and 0.12 ± 0.03 g/dL, respectively, p = 0.8321) nor the ratio (f(HNA-2) 3.6 ± 0.4 and 3.1 ± 0.8%, respectively, p = 0.0872) showed a significant difference between the two groups. To evaluate the impact of HMA on CVD incidence, we then divided the subjects into two groups on the basis of cHMA and f(HMA) value: cHMA C2.0 versus \2.0 g/dL and f(HMA) C55 versus \55%, respectively. The relationship between CVD incidence and HMA value (cHMA and f(HMA)) is shown in Fig. 1. CVD incidence was significantly higher in the group with the higher HMA value. In order to know if there are any risk factors affecting the redox state of HSA, we performed simple and multiple
123
632
Clin Exp Nephrol (2012) 16:629–635
Table 3 Serum albumin and its redox state
Total (n = 30)
CVD (-) (n = 22)
CVD (?) (n = 8)
p value
3.65 ± 0.52
3.81 ± 0.37
3.21 ± 0.64
0.0036**
Albumin (g/dL) Total cHMA
2.00 ± 0.49
2.16 ± 0.43
1.58 ± 0.39
0.0026**
cHNA-1
1.53 ± 0.29
1.53 ± 0.29
1.52 ± 0.31
0.9152
cHNA-2
0.12 ± 0.03
0.12 ± 0.03
0.12 ± 0.02
0.8321
f(HMA)
54.4 ± 8.5
56.4 ± 8.6
48.9 ± 5.4
0.0278*
f(HNA-1)
42.4 ± 8.0
40.5 ± 8.1
47.6 ± 5.2
0.0282*
f(HNA-2)
3.2 ± 0.7
3.1 ± 0.8
3.6 ± 0.4
0.0872
Redox state (%)
* p \ 0.05 and ** p \ 0.005 vs CVD (-) group
Fig. 1 The relationship between CVD incidence and HMA value. CVD incidence was significantly higher in lower HMA group, both in concentration (a cHMA) and in ratio (b f(HMA))
CVD, living (%) CVD, died (%)
A 50
B
40
17.6
50 40 17.6
30
30 p=0.0039
20
20
p=0.0399
29.4 10
10 p=0.0322 0
0 (n=13)
23.5
7.7 (n=17)
(n=13)
(n=17)
ƒ(HMA)
7.7 15.4 30.8
(stepwise forward) regression analysis, in which cHMA and f(HMA) were adopted as the criterion variables, whereas CRP, transferrin saturation, urea nitrogen, hemoglobin, age, primary disease (diabetes = 1), and usage of acid/high GDP solutions were the explanatory variables. Results are shown in Table 4. With regard to concentration (cHMA), CRP, transferrin saturation and age significantly correlated with cHMA in the simple regression analysis, whereas CRP and hemoglobin were selected as significant explanatory variables in the multiple regression analysis. With regard to fraction (f(HMA)), only UN significantly correlated with f(HMA) in the simple regression analysis, and likewise, only UN was selected as significant explanatory variable in the multiple regression analysis. Finally, we performed multiple logistic regression analysis in which CRP, hemoglobin, UN and cHMA (Model A) or f(HMA) (Model B) were determined to be the explanatory variables, whereas CVD incidence was the criterion variable. Results are shown in Table 5. Of these explanatory variables, only cHMA exhibited statistical significance in Model A (p = 0.0369, R = -0.260), whereas f(HMA) showed marginal significance in Model B (p = 0.0580, R = -0.214).
123
N. S. (p=0.2487)
0
cHMA
%elderly (age %diabetes %acidic solution
0
35.3 29.4 47.1
(p-value) 0.0813 0.3855 0.3842
7.7 7.7 23.1
35.3 35.3 52.9
(p-value) 0.0813 0.0813 0.1047
Discussion In this study, we showed that a lower level of reduced albumin is a powerful independent risk factor for serious CVD incidence among PD patients. From the view point of redox state of HSA, HSA is composed of HMA (reduced form) and HNA (oxidized form). Furthermore, HNA consists of HNA-1 (a major fraction, reversibly oxidized form) and HNA-2 (a minor fraction, irreversibly oxidized form). We have developed a convenient HPLC system for the clear separation of HSA into HMA and HNA [5, 6], and we have extensively studied the dynamic changes of HSA (Cys-34)-redox state under various physiologic [7–9] and pathophysiologic states, such as hepatic [10, 11], renal [2, 4, 12–14], diabetic [15], and other diseases [16–18]. The present study provides several lines of evidence to suggest that a lower HMA value powerfully influences the incidence and mortality of CVD. Formerly, the redox state of small-molecule thiols (glutathione and free cysteine) in plasma was reported to be the predictor for the presence of early athelosclerosis [19] and endothelial dysfunction [20]. Theoretically, the redox state of small-molecule thiols
Clin Exp Nephrol (2012) 16:629–635
633
Table 4 Correlation between cHMA, f(HMA) and clinical data cHMA
f (HMA)
Simple R C-reactive protein Transferrin saturation Urea nitrogen Creatinine
-0.522 0.403 -0.271 0.101
Multiple
Simple
Multiple
p value
R
p value
R
0.0026**
-0.528
0.0024**
-0.275
0.1417
0.205
0.2804
0.0264* 0.1480 0.5975
p value
-0.410 -0.139
0.0236* 0.4633
Uric acid
-0.133
0.4874
-0.260
0.1666
Beta 2-microgloblin
-0.186
0.3276
-0.259
0.1691
0.357
0.0523
0.331
0.0743
Hemoglobin
0.365
0.0206*
Age
-0.439
0.0145*
-0.323
0.0815
Primary disease (diabetes = 1)
-0.313
0.0922
-0.245
0.1938
Usage of acid/high-GDP solutions
-0.146
0.4459
-0.312
0.0935
R
p value
-0.410
0.0236*
*p \ 0.05 and **p \ 0.005
Table 5 Result of multiple logistic regression analysis in which CVD incidence was adapted as criterion variable
*p \ 0.05
Model A v
2
Model B R
p value
v2
R
p value
Constant
3.252
0.190
0.0713
3.202
0.186
0.0735
C-reactive protein
0.002
0.000
0.9616
0.666
0.000
0.4143
Hemoglobin
0.019
0.000
0.8902
0.182
0.000
0.6696
Urea nitrogen cHMA
1.829 4.357
0.000 -0.260
0.1762 0.0369*
1.969
0.000
0.1605
3.594
-0.214
0.0580
f(HMA)
depends mainly on that of HSA, because a large portion of the thiol groups in human extracellular fluid is primarily derived from HMA, as mentioned above. In this context, an insufficiency of HMA might lead to CVD events via subclinical atherosclerosis and endothelial dysfunction. In the present study, higher CRP and lower hemoglobin were selected as dependent contributors of lower HMA concentration (cHMA), whereas higher UN was selected as a dependent contributor of lower HMA ratio (f(HMA)). From these findings, chronic inflammation, anemia, and accumulation of some dialyzable uremic toxin(s) might be regarded as potential causable factors of the decrease of HMA. Chronic inflammation is common in CKD patients and is reported to be induced, at least in part, by micro-endotoxemia in CKD patients before dialysis [21], on HD [22], and on PD [23]. In the inflammatory state, hepatic cells mainly synthesize CRP instead of unmodified albumin = HMA. Therefore, it is reasonable that chronic inflammation reduces HMA value via suppression of synthesis, as in the case of liver cirrhosis [11]. Anemia is also common in CKD patients. It is reported that anemia is related to elevation of the level of
malonyldialdehyde (the marker of lipid peroxidation by radicals) in CKD patients on hemodialysis [24]. Considering that radical generation from neutrophils is accelerated in CKD patients [25], and that the liver uptake clearance of ‘oxidized’ albumin is reported to be increased by 11-fold [26], anemia might reduce HMA value via oxidation. With regard to the relationship between dialyzable uremic toxin(s) and decrease of HMA, we previously reported this relationship in the clinical setting such as predialysis [12], HD [2] and PD patients [13]. Recently, we found from cell culture experiments that aortic endothelial cells actively generate the thiol-disulfide exchange reaction, i.e., the HNA-1 ? HMA conversion of human albumin [27], while such a reaction is suppressed by methylglyoxal [28], one of the representative dialyzable uremic toxins [29]. Therefore, theoretically, it is supposed that accumulation of dialyzable uremic toxins, such as methylglyoxal, reduces HMA value via suppression of HSA reduction by the endothelial cells of whole blood vessels. With regard to the reason why the risk factors for low cHMA (inflammation and anemia) and for low f(HMA) (high UN) were different in this study, we suspect that such
123
634
Clin Exp Nephrol (2012) 16:629–635
a difference reflects the difference of mechanism of lowering HMA; the decline of cHMA might reflect accelerated oxidation of HMA, whereas the decline of f(HMA) might reflect impaired reductive potential of the body for HNA. The present study revealed that a lower level of HMA (both cHMA and f(HMA)) is correlated with future occurrence of CVD. At present, it is unclear whether low HMA is (one of) a cause of CVD occurrence, or only a surrogate of bad condition. However, we suspect that low HMA is really a cause of CVD occurrence, because HMA acts in the body as the strongest extracellular antioxidant [3], and because cHNA (oxidized or impaired albumin) was not increased in CVD patients as shown in Table 3. This concern should be proved by a future interventional approach to increase HMA level [30]. There are some important limitations in this study. Firstly, the cohort size is too small to estimate accurate degree of risk caused by HSA (Cys-34)-oxidation. Secondary, the present study was a single center study. Thus, further study based on a larger size multi-center cohort is an issue to be clarified in the future. Conflict of interest
None.
References 1. Nakai S, Suzuki K, Masakane I, Wada A, Itami N, Ogata S, et al. Overview of regular dialysis treatment in Japan (as of 31 December 2008). Ther Apher Dial. 2010;14:505–40. 2. Terawaki H, Takada Y, Era S, Funakoshi Y, Nakayama K, Nakayama M, et al. The redox state of albumin and serious cardiovascular incidence in hemodialysis patients. Ther Apher Dial. 2010;14:465–71. 3. Ogasawara Y, Namai T, Togawa T, Ishii K. Formation of albumin dimers induced by exposure to peroxides in human plasma: a possible biomarker for oxidative stress. Biochem Biophys Res Commun. 2005;340:353–8. 4. Terawaki H, Nakayama K, Matsuyama Y, Nakayama M, Sato T, Hosoya T, et al. Dialyzable uremic solutes contribute to enhanced oxidation of serum albumin in regular hemodialysis patients. Blood Purif. 2007;25:274–9. 5. Sogami M, Nagoka S, Era S, Honda M, Noguchi K. Resolution of mercapt- and nonmercaptalbumin by high-performance liquid chromatography. Int J Peptide Protein Res. 1984;24:96–103. 6. Sogami M, Era S, Nagaoka S, Kuwata K, Kida K, Miura K, et al. HPLC-studies on nonmercapt–mercapt conversion of human serum albumin. Int J Peptide Protein Res. 1985;25:398–402. 7. Era S, Hamaguchi T, Sogami M, Kuwata K, Suzuki E, Miura K, et al. Further studies on the resolution of human mercapt- and non-mercaptalbumin and on human serum albumin in the elderly by high-performance liquid chromatography. Int J Peptide Protein Res. 1988;31:435–42. 8. Era S, Kuwata K, Imai I, Nakamura K, Hayashi T, Sogami M. Age-related change in redox state of human serum albumin. Biochim Biophys Acta. 1995;1247:12–6. 9. Imai H, Hayashi T, Negawa T, Nakamura K, Tomida M, Koda K, et al. Strenuous exercise-induced change in redox state of human serum albumin during intensive kendo training. Jpn J Physiol. 2002;52:135–40.
123
10. Sogami M, Era S, Nagaoka S, Kuwata K, Kida K, Shigemi J, et al. High-performance liquid chromatographic studies on nonmercapt in equilibrium with mercapt conversion of human serum albumin. II. J Chromatogr. 1985;332:19–27. 11. Fukushima H, Miwa Y, Shiraki M, Gomi I, Toda K, Kuriyama S, et al. Oral branched-chain amino acid supplementation improves the oxidized/reduced albumin ratio in patients with liver cirrhosis. Hepatol Res. 2007;37:765–70. 12. Terawaki H, Yoshimura K, Hasegawa T, Matsuyama Y, Negawa T, Yamada K, et al. Oxidative stress is enhanced in correlation with renal dysfunction: examination with the redox state of albumin. Kidney Int. 2004;66:1988–93. 13. Terawaki H, Matsuyama Y, Era S, Matsuo N, Ikeda M, Ogura M, et al. Elevated oxidative stress measured as albumin redox state in continuous ambulatory peritoneal dialysis patients correlates with small uraemic solutes. Nephrol Dial Transpl. 2007; 22:968. 14. Matsuyama Y, Terawaki H, Terada T, Era S. Albumin thiol oxidation and serum protein carbonyl formation are progressively enhanced with advancing stages of chronic kidney disease. Clin Exp Nephrol. 2009;13:308–15. 15. Suzuki E, Yasuda K, Takeda N, Sakata S, Era S, Kuwata K, et al. Increased oxidized form of serum albumin in patients with diabetes mellitus. Diabetes Res Clin Pract. 1992;18:153–8. 16. Hayakawa A, Kuwata K, Era S, Sogami M, Shimonaka H, Yamamoto M, et al. Alteration of redox state of human serum albumin in patients under anesthesia and invasive surgery. J Chromatogr B. 1997;698:27–33. 17. Kawai K, Yoh M, Hayashi T, Imai H, Negawa T, Tomida M, et al. Observation for redox state of human serum and aqueous humor albumin from patients with senile cataract. Tokai J Exp Clin Med. 2001;26:93–9. 18. Tomida M, Ishimaru J, Murayama K, Kajimoto T, Kurachi M, Era S, et al. Intra-articular oxidative state correlated with the pathogenesis of disorders of the temporomandibular joint. Br J Oral Maxillofac Surg. 2004;42:405–9. 19. Ashfaq S, Abramson JL, Jones DP, Rhodes SD, Weintraub WS, Hooper WC, et al. The relationship between plasma levels of oxidized and reduced thiols and early athelosclerosis in healthy adults. J Am Coll Cardiol. 2006;47:1005–11. 20. Ashfaq S, Abramson JL, Jones DP, Rhodes SD, Weintraub WS, Hooper WC, et al. Endothelial function and aminothiol biomarkers of oxidative stress in healthy adults. Hypertension. 2008;52:80–5. 21. Gonc¸alves S, Pecoits-Filho R, Perreto S, Barberato SH, Stinghen AE, Lima EG, et al. Associations between renal function, volume status and endotoxaemia in chronic kidney disease patients. Nephrol Dial Transpl. 2006;21:2788–94. 22. Terawaki H, Yokoyama K, Yamada Y, Maruyama Y, Iida R, Hanaoka K, et al. Low-grade endotoxemia is contributing to chronic inflammation in hemodialysis patients: examination with the novel LPS detection method (ESP method). Ther Apher Dial. 2010;14:477–82. 23. Szeto CC, Kwan BCH, Chow KM, Lai KB, Chung KY, Leung CB, et al. Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients. Clin J Am Soc Nephrol. 2008;3:431–6. 24. Sommerburg O, Grune T, Hampl H, Riedel E, van Kuijk FJ, Ehrich JH, et al. Does long-term treatment of renal anemia with recombinant erythropoietin influence oxidative stress in haemodialysed patients? Nephrol Dial Transpl. 1998;13:2583–7. 25. Sela S, Shurtz-Swirski R, Cohen-Mazor M, Mazor R, Chezar J, Shapiro G, et al. Primed peripheral polymorphonuclear leukocyte: a culprit underlying chronic low-grade inflammation and systemic oxidative stress in chronic kidney disease. J Am Soc Nephrol. 2005;16:2431–8.
Clin Exp Nephrol (2012) 16:629–635 26. Anraku M, Kragh-Hansen U, Kawai K, Mariyama T, Yamasaki Y, Takakura Y, et al. Validation of the chloramine-T induced oxidation of human serum albumin as a model for oxidative damage in vivo. Pharm Res. 2003;20:684–92. 27. Matsuyama Y, Hayashi T, Terawaki H, Negawa T, Terada T, Okano Y, et al. Human astrocytes and aortic endothelial cells actively convert the oxidized form of albumin to the reduced form: reduced albumin might participate in redox regulation of nerve and blood vessel systems. J Physiol Sci. 2009;59:207–15. 28. Terawaki H, Era S, Nakayama M, Hosoya T. Decrease in reduced-form albumin among chronic kidney disease patients:
635 new insights in cardiovascular complications. Ther Apher Dial. 2011;15:156–60. 29. Nakayama K, Nakayama M, Iwabuchi M, Terawaki H, Sato T, Kohno M, et al. Plasma a-oxoaldehyde levels in diabetic and nondiabetic chronic kidney disease. Am J Nephrol. 2008;28: 1871–8. 30. Tanaka M, Tokunaga K, Komaba H, Itoh K, Matsushita K, Watanabe H, et al. Vitamin D receptor activator reduces oxidative stress in hemodialysis patients with secondary hyperparathyroidism. Ther Apher Dial. 2011;15:161–8.
123
