Effect of intravenous iron administration frequency on AOPP and inflammatory biomarkers in chronic hemodialysis patients: A pilot study

doi:10.1016/j.clinbiochem.2008.07.007

Clinical Biochemistry

Volume 41, Issues 14–15, October 2008, Pages 1168-1174

https://doi.org/10.1016/j.clinbiochem.2008.07.007 Get rights and content

Abstract

Objectives

Intravenous iron administration (IVIR) is effective for correcting anemia in hemodialysis (HD) patients, but it also enhances the generation of hydroxyl radicals. Previously we demonstrated that IVIR increases oxidized serum albumin levels in HD patients. However, the effect of IVIR frequencies on the oxidative stress has never been studied before. Therefore, we compared the two IVIR schedules recommended by the Japanese Society for Dialysis Therapy guideline 2004 by measuring oxidized albumin in chronic HD patients.

Design and methods

Twenty-two HD patients were divided into two IVIR protocol groups (group I: 40 mg of iron 3 times a week for 4 weeks, group II: 40 mg of iron once a week for 3 months). These protocols differ in IVIR frequency, but receive the same amount of iron (total 520 mg). We compared these two regimens by determining the levels of hemoglobin, serum ferritin, advanced oxidation protein products (AOPP), and oxidized albumin at 0, 4, 8, 12, 16, and 20 weeks.

Results

Both patient groups resulted in a similar and significant increase in hemoglobin levels, whereas group I markedly induced AOPP and oxidation of serum albumin than group II at 4 weeks (P < 0.05). AOPP and oxidation of serum albumin was also gradually declined by 20 weeks, while the oxidized albumin and AOPP in group II was not significantly changed during the entire experimental period. Transferrin saturation and serum ferritin levels were also increased in group I compared with group II at 4 weeks (P < 0.001). In addition, we found a strong positive correlation between oxidized albumin and serum ferritin levels (r = 0.615, P < 0.05), suggesting the possibility that the accumulation of iron stores has a causative role in the progression of oxidative stress in HD patients treated with IVIR.

Conclusions

The results of this study indicate that lower frequency IVIR protocol is recommended to reduce IVIR-induced oxidative stress in HD patients.

Introduction

In patients who are on chronic hemodialysis (HD), anemia is a major complication and is associated with poor clinical outcomes. Consequently, management of anemia by recombinant erythropoietin is reported consistently to improve outcome measures in HD patients. Because iron is essential for hemoglobin formation, as is erythropoietin, most patients routinely receive iron intravenously (IVIR) for anemia correction. Although IVIR has been shown to improve both survival and quality of life of HD patients [1], [2], [3], it has been suggested that IVIR may enhance the generation of hydroxyl radicals in the body through the inflammation process and the Fenton reaction [4], [5]. Oxidative stress, which involves the production of excessive levels of reactive oxygen spices (ROS) is closely related to the progression of renal failure [6]. Furthermore, the management of cardiovascular disease (CVD) is an important issue in cases of HD patients, and oxidative stress has been speculated to greatly contribute to such onset [7]. Since plasma proteins are extremely susceptible to oxidative stress, biomarkers for protein oxidation such as advanced protein oxidation products (AOPP) or carbonyl contents have recently been applied to assess the oxidative stress in the pathological conditions [8], [9], [10], [11]. Tovbin et al. reported that IVIR in HD patients induced an increase in the level of protein oxidation products, as assessed by AOPP levels and that this effect is positively related to the inflammatory state of patients [12]. AOPP levels also have been described as an independent risk factor for coronary artery disease, in part because its plasma levels are significantly related to coronary artery pathology [13]. Therefore, they might propose that IVIR and inflammation synergistically induce not only oxidative stress but also coronary artery disease. The high-performance liquid chromatographic (HPLC) analysis of serum albumin developed by Sogami et al. permits the clear separation of human serum albumin (HSA) into mercaptalbumin (HMA; reduced form) and nonmercaptalbumin (HNA; oxidized form) [14], [15], and is used for the determination of the redox state for various pathophysiological conditions [16], [17], [18], [19]. In 2001, Himmelfarb and McMonagle [20] reported, for the first time, that the oxidation of albumin accounts for almost all of the excess plasma protein oxidation in uremic patients as evidenced by SDS-PAGE and an immunoassay using an anti-2,4 dinitrophenylhydrazine (DNP) antibody developed by Shacter et al. [21], [22]. Previously we also demonstrated that serum albumin is highly oxidized in HD patients with an increase in the disulfide form by using HPLC analysis and that IVIR on these patients significantly increased the oxidation status of albumin, as evidenced by a marked increase in the oxidized form [23].

In 2004, the committee on the guidelines of the Japanese Society for Dialysis Therapy (JSDT) published the original Japanese “Guidelines for Renal Anemia in Chronic Hemodialysis Patients” [24]. In the JSDT guidelines 2004, the committee recommended two IVIR schedules for iron deficient patients; 1) administer 40 mg of IV iron at the end of dialysis session 3 times a week for 4 weeks (total 520 mg of iron), 2) administer 40 mg of IV iron at the end of dialysis session once a week for 3 months (total 520 mg of iron). Both administration schedules are effective for the correction of iron deficiency and consequently for the amelioration of anemia. However, the effect of IVIR frequency (3 times a week vs. once a week) on the oxidative stress formation has not been investigated before. Therefore, we compared the two IVIR schedules recommended by the JSDT guideline 2004 by measuring oxidized albumin in chronic HD patients.

Section snippets

Patients

The protocol used in this study was approved by the institutional review board of Kumamoto University and informed consent was obtained from all patients. Iron deficiency anemia was defined as low hemoglobin level (< 10.0 g/dL), low serum ferritin level (≤ 100 ng/mL), and low transferrin saturation ratio (≤ 20%) according to the JSDT guideline 2004. Twenty-two stable HD patients with iron deficiency anemia (11 men, 11 women) aged 47 to 85 years, with a dialysis period ranging between 2 and 11

Effect of IVIR frequency on anemia correction

Table 1 shows characteristics of the patient groups. Patient groups did not differ in respect to age, gender, diabetes/non-diabetes ratio, duration and efficacy of hemodialysis. Both IVIR groups had similar basal hemoglobin (Hgb) and hematocrit (Hct) levels at 0 week (Table 1). As shown in Fig. 1, Hgb and Hct levels were substantially increased by IVIR with statistical significance at 4, 8, 12, 16, and 20 weeks compared with 0 week (P < 0.05). Both Hgb and Hct were peaked at 12 weeks (group I:

Discussion

Cardiovascular diseases continue to be the major cause of both morbidity and mortality for patients on HD therapy. For HD patients, the annual mortality rate caused by cardiovascular disorders is approximately 9%, which is 10- to 20-fold higher than the general population, even when adjusted for age, sex, race, and the presence or absence of diabetes [25]. A potential link between inflammation, hypoalbuminemia, and subsequent cardiovascular risk in HD patients may be through the process of

Acknowledgments

The authors thank Dr. Shunichi Sakaguchi (Midorigaoka Clinic, Kumamoto, Japan) for the blood sample collection from HD patients and for the helpful discussions. This work was supported by the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan (19590956 to K.K., 14370759 and 14657618 to M.O.), Salt Science Research Foundation Grant (0728 to K.K.), Mitsubishi Pharma Research Foundation Grant (to K.K.), and the Grant from The

References (33)

S. Fishbane et al.
Iron management in end-stage renal disease
Am J Kidney Dis
(1997)
B. Halliwell
Superoxide-dependent formation of hydroxyl radicals in the presence of iron salts. Its role in degradation of hyaluronic acid by a superoxide-generating system
FEBS Lett
(1978)
U. Singh et al.
Oxidative stress and atherosclerosis
Pathophysiology
(2006)
V. Witko-Sarsat et al.
AOPP-induced activation of human neutrophil and monocyte oxidative metabolism: a potential target for N-acetylcysteine treatment in dialysis patients
Kidney Int
(2003)
V. Witko-Sarsat et al.
Are advanced oxidation protein products potential uremic toxins?
Kidney Int
(2003)
V. Witko-Sarsat et al.
Advanced oxidation protein products as a novel marker of oxidative stress in uremia
Kidney Int
(1996)
P. Odetti et al.
Protein oxidation in hemodialysis and kidney transplantation
Metabolism
(1996)
D. Tovbin et al.
Induction of protein oxidation by intravenous iron in hemodialysis patients: role of inflammation
Am J Kidney Dis
(2002)
H. Kaneda et al.
Increased level of advanced oxidation protein products in patients with coronary artery disease
Atherosclerosis
(2002)
A. Hayakawa et al.
Alteration of redox state of human serum albumin in patients under anesthesia and invasive surgery
J Chromatogr B Biomed Sci Appl
(1997)

M. Sogami et al.

High-performance liquid chromatographic studies on non-mercapt in equilibrium with mercapt conversion of human serum albumin. II

J Chromatogr

(1985)

E. Suzuki et al.

Increased oxidized form of human serum albumin in patients with diabetes mellitus

Diabetes Res Clin Pract

(1992)

A. Soejima et al.

Useful markers for detecting decreased serum antioxidant activity in hemodialysis patients

Am J Kidney Dis

(2002)

J. Himmelfarb et al.

Albumin is the major plasma protein target of oxidant stress in uremia

Kidney Int

(2001)

Y. Lee et al.

Role of carbohydrates in oxidative modification of fibrinogen and other plasma proteins

Arch Biochem Biophys

(1995)

E. Shacter et al.

Differential susceptibility of plasma proteins to oxidative modification: examination by western blot immunoassay

Free Radic Biol Med

(1994)

Cited by (40)

Reticulocyte hemoglobin content
2020, Clinica Chimica Acta
Iron deficiency leads to the suppression of hemoglobin (Hb) synthesis and induces metabolic disorders. In contrast, iron overload not only reduces the iron utilization efficiency but also induces oxidative stress. Iron metabolism in the body is closely regulated by hepcidin, a short peptide produced by the liver. Unfortunately, conventional iron indices may not always accurately reflect the iron status. For example, Hb concentration assessed using mature erythrocytes do not accurately reflect the real-time iron status due to their long lifespan. Reticulocytes are differentiated from erythroblasts after Hb synthesis and transform into mature erythrocytes in 1–2 days upon release into peripheral blood. Thus, Hb content in reticulocytes (Hb-ret) is more reflective of real-time Hb synthesis. Moreover, Hb-ret is affected only by the amount of iron intake as long as there is no hematopoietic disorder. Reticulocyte Hb content (CHr) can be accurately and inexpensively measured as Hb-ret by commercial H*3 or ADVIA hematology analyzers. CHr has been shown to be more effective than other indices of iron metabolism for the diagnosis of iron deficiency, for early detection of the therapeutic effects of iron therapy, and for differentiation of the beta thalassemia trait.
Clinical Implications Associated With the Posttranslational Modification–Induced Functional Impairment of Albumin in Oxidative Stress–Related Diseases
2017, Journal of Pharmaceutical Sciences
Recent research findings indicate that the posttranslational modification of human serum albumin (HSA) such as oxidation, glycation, truncation, dimerization, and carbamylation is related to certain types of diseases. We report herein on a simple and rapid analytical method, using an electrospray ionization time-of-flight mass spectrometry technique, that allows posttranslational modifications of HSA to be quantitatively and qualitatively evaluated with a high degree of sensitivity. In patients with chronic liver disease, chronic renal disease, and diabetes mellitus, an increase in the level of oxidized cysteine-34 (Cys-34) of HSA accompanied by a decrease in the level of reduced Cys-34 was observed. The redox status of Cys-34 was correlated with ligand binding and the antioxidative functions of HSA. Available evidence indicates that monitoring the redox state of Cys-34 not only could be a useful marker for evaluating the progression of disease and its complications but also would permit therapeutic efficacy to be predicted. The redox state of Cys-34 was also used as an index of the quality of HSA preparations. These data suggest that monitoring the posttranslational modifications of HSA can be important, because the function of HSA is related not only to its serum concentration but also to the preservation of its structural integrity under disease conditions.
Human serum albumin hydropersulfide is a potent reactive oxygen species scavenger in oxidative stress conditions such as chronic kidney disease
2016, Biochemical and Biophysical Research Communications
Citation Excerpt :
Human serum albumin (HSA) is the most abundant serum protein possessing 34 cysteines forming 17 disulfide bonds, and only one reduced cysteine at the position 34 (Cys-34). The degree of oxidized Cys-34 in HSA correlates with oxidative stress related pathological conditions, and the oxidation-reduction status of Cys-34 has been shown to be useful in assessing the level of oxidative stress in diseased states and for evaluating the anti-oxidative activity of a therapeutic agent [8–11]. Furthermore, oxidized Cys-34 in HSA could potentially form a stable persulfide [3].
Recently, hydropersulfide (RSSH) was found to exist in mammalian tissues and fluids. Cysteine hydropersulfide can be found in free cysteine residues as well as in proteins, and it has potent antioxidative activity. Human serum albumin (HSA) is the most abundant protein in mammalian serum. HSA possesses a free thiol group in Cys-34 that could be a site for hydropersulfide formation. HSA hydropersulfide of high purity as a positive control was prepared by treatment of HSA with Na₂S. The presence of HSA hydropersulfide was confirmed by spectroscopy and ESI-TOFMS analysis where molecular weights of HSA hydropersulfide by increments of approximately 32 Da (Sulfur atom) were detected. The fluorescent probe results showed that Alexa Fluor 680 conjugated maleimide (Red-Mal) was a suitable assay and bromotrimethylammoniumbimane bromide appeared to be a selective reagent for hydropersulfide. The effect of oxidative stress related disease on the existence of albumin hydropersulfides was examined in rat 5/6 nephrectomy model of chronic kidney disease (CKD). Interestingly, the level of hydropersulfides in rat 5/6 nephrectomy model serum was decreased by a uremic toxin that increases oxidative stress in rat 5/6 nephrectomy model. Furthermore, we demonstrated that the levels of HSA hydropersulfide in human subjects were reduced in CKD but restored by hemodialysis using Red-Mal assay. We conclude that HSA hydropersulfide could potentially play an important role in biological anti-oxidative defense, and it is a promising diagnostic and therapeutic marker of oxidative diseases.
Human plasma lipocalins and serum albumin: Plasma alternative carriers?
2016, Journal of Controlled Release
Citation Excerpt :
The reduced binding capacity of HSA in uremic patients may reflect the combination of direct and indirect binding effects of FAs and uremic toxins [184]. The enhanced oxidative stress reported in patients with end-stage renal disease may cause cardiovascular complications since HSA is structurally and functionally altered [13,14]. The occurrence of oxidative damages has been reported also in individuals affected by the acute respiratory distress syndrome [203] (Table 1).
Lipocalins are an evolutionarily conserved family of proteins that bind and transport a variety of exogenous and endogenous ligands. Lipocalins share a conserved eight anti-parallel β-sheet structure. Among the different lipocalins identified in humans, α-1-acid glycoprotein (AGP), apolipoprotein D (apoD), apolipoprotein M (apoM), α1-microglobulin (α1-m) and retinol-binding protein (RBP) are plasma proteins. In particular, AGP is the most important transporter for basic and neutral drugs, apoD, apoM, and RBP mainly bind endogenous molecules such as progesterone, pregnenolone, bilirubin, sphingosine-1-phosphate, and retinol, while α1-m binds the heme. Human serum albumin (HSA) is a monomeric all-α protein that binds endogenous and exogenous molecules like fatty acids, heme, and acidic drugs. Changes in the plasmatic levels of lipocalins and HSA are responsible for the onset of pathological conditions associated with an altered drug transport and delivery. This, however, does not necessary result in potential adverse effects in patients because many drugs can bind both HSA and lipocalins, and therefore mutual compensatory binding mechanisms can be hypothesized. Here, molecular and clinical aspects of ligand transport by plasma lipocalins and HSA are reviewed, with special attention to their role as alterative carriers in health and disease.
Plasma protein thiolation index (PTI) as a biomarker of thiol-specific oxidative stress in haemodialyzed patients
2015, Free Radical Biology and Medicine
The role of oxidative stress in patients with end stage renal disease (ESRD), which occurs at significantly higher levels than in the general population, is often underestimated in clinical practice. Emerging evidence highlights the strong correlation of oxidative stress with chronic inflammation and cardiovascular disease, which are highly prevalent in most patients on maintenance haemodialysis (HD) and are a major risk factor for mortality in this population. In this study, total plasma thiols and plasma S-thiolated proteins were measured in patients with ESRD, before and after a regular HD session, and compared to age-matched healthy subjects. We found a significant decrease in the level of total plasma thiols and, conversely, a significant increase in the level of S-thiolated proteins in these patients. In most patients, post-HD plasma level of total thiols did not differ from the one in healthy subjects, whereas plasma level of S-thiolated proteins was lower in HD patients than in age-matched healthy controls. This suggests that a single HD session restores plasma thiol redox status and re-establishes the antioxidant capacity of plasma thiols. Additionally, we determined protein thiolation index (PTI), i.e., the molar ratio between the sum of all low molecular mass thiols bound to S-thiolated plasma proteins and protein free cysteinyl residues. Patients with ESRD had a significantly higher PTI compared to age-matched healthy subjects and HD was associated with a decrease in PTI to normal, or lower than normal, levels. Although this study is limited in size, our results suggest that PTI is a useful indicator of thiol-specific oxidative stress in patients with ESRD on maintenance HD. This study also emphasizes that PTI determination is a cheap and simple tool suitable for large-scale clinical studies that could be used for routine screening of thiol-specific oxidative stress.
Long-Term Safety and Efficacy of a Novel Iron-Containing Phosphate Binder, JTT-751, in Patients Receiving Hemodialysis
2014, Journal of Renal Nutrition
Citation Excerpt :
Despite the apparent safety of JTT-751, iron status in patients treated with JTT-751 should be monitored regularly. Intravenous iron preparations have also been reported to increase oxidative stress, which is linked to various diseases,24 and some reports have shown that reducing the frequency of administration of intravenous preparations leads to a decrease in oxidative stress.25 In this study, the dose of intravenous iron preparations was markedly decreased by administration of JTT-751.
JTT-751 is a novel phosphate binder containing ferric citrate as the active ingredient. This study investigated long-term safety and efficacy of JTT-751 for hyperphosphatemia in patients receiving hemodialysis.
This was 52-week, phase 3, multicenter, open-label, dose titration, long-term study. All patients were receiving thrice-weekly hemodialysis for ≥3 months before the initiation of the study. JTT-751 was given at titrated doses between 1.5 and 6.0 g/day.
Safety endpoints were adverse events and adverse drug reactions. Efficacy outcomes were the change in serum phosphate, corrected serum calcium, and intact parathyroid hormone. Changes in ferritin, transferrin saturation, and doses of erythropoiesis-stimulating agents (ESAs) and intravenous iron formulations were additional outcomes.
One hundred and eighty patients were included in the trial. Dose-titrated JTT-751 decreased mean serum phosphate after administration and satisfactorily maintained serum phosphate concentrations throughout the entire duration of the 52-week trial. Mean serum phosphate concentrations were kept lower than 5.5 mg/dL from weeks 5 to 52. The most common adverse events were gastrointestinal disorders, which were mild to moderate in intensity. Serum ferritin concentrations rose to a peak around week 28 and stabilized thereafter. The mean intravenous iron dose decreased from 57.3 mg/4 weeks (weeks 0-12) to 3.6 mg/4 weeks (weeks 28-52); weekly ESA dose declined by 25% over the same time frame, while mean hemoglobin concentrations remained stable.
JTT-751 1.5-6.0 g/day controls serum phosphorus concentrations and reduces the need for ESAs and intravenous iron in patients receiving hemodialysis.

View all citing articles on Scopus

¹: M. Anraku and K. Kitamura contributed equally to this work.

²: K. Tomita and M. Otagiri contributed equally to this work.

View full text

Effect of intravenous iron administration frequency on AOPP and inflammatory biomarkers in chronic hemodialysis patients: A pilot study

Abstract

Objectives

Design and methods

Results

Conclusions

Introduction

Section snippets

Patients

Effect of IVIR frequency on anemia correction

Discussion

Acknowledgments

Am J Kidney Dis

FEBS Lett

Pathophysiology

Kidney Int

Kidney Int

Kidney Int

Metabolism

Am J Kidney Dis

Atherosclerosis

J Chromatogr B Biomed Sci Appl

J Chromatogr

Diabetes Res Clin Pract

Am J Kidney Dis

Kidney Int

Arch Biochem Biophys

Free Radic Biol Med