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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 5  |  Page : 930-937
Relation of middle molecules levels and oxidative stress to erythropoietin requirements in high-flux versus low-flux hemodialysis

1 Department of Nephrology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
3 Department of Nephrology, Ras El-Teen Hospital, Alexandria, Egypt

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Date of Web Publication12-Sep-2013


The objective of this study is to investigate the serum beta-2-microglobulin (B2MG) and advanced oxidation protein products (AOPP) as middle molecule uremic toxins and protein carbonyl (PCO) as oxidative stress marker in uremic patients undergoing high-flux versus low-flux hemodialysis (HD) and to correlate their levels to the erythropoietin requirements for those patients. Twenty patients on chronic low-flux HD were recruited in the study. At the start of the study, all patients underwent high-flux HD for eight weeks, followed by low-flux HD for two weeks as a washout period. The patients were then subjected to another eight weeks of low-flux HD. Blood samples were obtained at the beginning and at the end of the high-flux period and the low-flux period. The mean erythropoietin dose for patients using high-flux HD was significantly lower than that for low-flux HD (P = 0.0062). Post-high flux, the B2MG and PCO levels were significantly lower than the pre-high-flux levels (P = 0.026 and 0.0005, respectively), but no significant change was observed in AOPP (P = 0.68). Post-low flux, the B2MG, AOPP and PCO were significantly higher than the pre-low-flux levels (P = 0.0002, 0.021 and <0.0001, respectively). Post-low flux, the B2MG and PCO were significantly higher than the post-high-flux levels (P <0.0001), but no significant difference was observed in AOPP (P = 0.11). High-flux HD results in reduction of some of the middle molecule toxins and PCO levels better than low-flux HD, and is associated with a better response to erythropoietin.

How to cite this article:
El-Wakil HS, Abou-Zeid AA, El-Gohary IE, Abou El-Seoud NA. Relation of middle molecules levels and oxidative stress to erythropoietin requirements in high-flux versus low-flux hemodialysis. Saudi J Kidney Dis Transpl 2013;24:930-7

How to cite this URL:
El-Wakil HS, Abou-Zeid AA, El-Gohary IE, Abou El-Seoud NA. Relation of middle molecules levels and oxidative stress to erythropoietin requirements in high-flux versus low-flux hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2020 Dec 5];24:930-7. Available from: https://www.sjkdt.org/text.asp?2013/24/5/930/118082

   Introduction Top

The uremic syndrome is characterized by retention of toxins that adversely affect various metabolic processes and contribute to the associated morbidity and mortality, and they vary according to their sizes and hydrophobicity. [1],[2]

Middle molecules include beta-2 microglobulin (B2MG), advanced glycation end products (AGE), advanced oxidation protein products (AOPP) and other peptides. High-flux dialysis using membranes that have large pores may allow more efficient removal of these middle molecules than low-flux dialysis that uses membranes with smaller pore sizes. [2]

B2MG forms the beta chain of the human leukocyte antigen class I molecule. It is present on the surface of most nucleated cells and in most biological fluids. [3] It is mainly excreted by the kidney, with negligible extrarenal elimination. B2MG has a molecular weight of 11.8 kDa and has been widely used for assessment of dialysis efficiency as regards middle molecule removal. [4] Longstanding increases in serum B2MG levels are associated with the development of dialysis-related amyloidosis in patients on chronic hemodialysis (HD). [5],[6]

During dialysis, blood contact with the dialyzer membrane results in the activation of mono-nuclear cells and neutrophils. This results in the generation of large amounts of reactive oxygen species (ROS). The resulting oxidative stress is implicated in the accelerated atherogenesis and increased cardiovascular disease seen in patients on chronic HD. [7],[8],[9]

AOPP are uremic toxins created during oxidative stress through the reaction of chlorinated oxidants with plasma proteins. [10] Oxidation of amino acid residues such as tyrosine results in the formation of dityrosine, protein cross-linking and fragmentation and loss of enzymatic or other functional properties. [7],[11] Advanced oxidation protein products have variable molecular weights depending on the ligand to which they are linked. [1] Besides being markers of oxidative stress, AOPP appear to have a pro-inflammatory action. [12]

Oxidation of carbohydrates and lipids may lead to the production of reactive carbonyl groups (RCOs). The association of ROS and RCOs with proteins may result in the formation of carbonylated dysfunctional proteins in plasma and tissues. [11] Protein carbonyl (PCO) content is considered a good marker of oxidative stress-dependent cellular damage. [13] A general increase in plasma PCOs in uremic patients has been reported. [8],[14] Besides, PCOs are precursors of advanced glycation end-products (AGE), which constitute a middle molecule toxin that plays a vital role in the progression of renal failure. [15],[16]

The aim of our study was to investigate the effect of high-flux versus low-flux HD on the serum levels of uremic toxins B2MG and advanced oxidation protein products as well as the oxidative stress marker PCO in chronic HD patients.

   Patients and Methods Top

Twenty patients (16 males and four females) were recruited from the El-Shefaa Hospital in Alexandria, Egypt. All the patients were in a stable clinical condition. A group of 20 healthy age-matched subjects were included as a control group.

We included in the study adult CKD patients with the following criteria: On chronic HD, on maintenance dose of human recombinant erythropoietin (epoetin beta-Recormon) after reaching target hemoglobin (11-12 g/dL) and on adequate dialysis with urea reduction ratio >65%. We excluded patients with iron deficiency or blood loss, uncontrolled hyperpara-thyroidism, infection or inflammation, aluminum toxicity, vitamin B 12 , folate or carnitine deficiency, bone marrow disorders or hemoglobinopathies, erythropoietin antibodies (PRCA) or on anti-inflammatory or antioxidant therapy in addition to smokers.

Informed consent was obtained from all participants in the study. The study was approved by the ethics committee of the Faculty of Medicine, Alexandria University.

The study was of a cross-over design. Before starting the study, all patients were on chronic regular low-flux HD. At the beginning of the study, all the patients were switched to high-flux HD for a period of eight weeks (Period A). This was followed by a washout period (Period W) of two weeks on low-flux HD. Then, the patients were maintained on low-flux HD for a further period of eight weeks (Period B). Because different membrane types may have different effects on the oxidative status in HD patients, [17] both high-flux and low-flux membranes were made of the same surface area and the same material (synthetic polyamide blend membranes: Polyflux 170H and polyflux 17L, respectively).

Full medical history and clinical examination were carried out on all patients in addition to complete blood investigations every four weeks during the study. Erythropoietin dose was adjusted to maintain the hemoglobin level at 11-12 g/dL. Pre- and post-dialysis serum urea were measured every four weeks to calculate the urea reduction ratio: URR = (Urea pre-dialysis - Urea post-dialysis) / Urea pre-dialysis × 100.

Pre-dialysis blood samples were obtained before the first dialysis session of the high-flux period A (pre-high flux), at the end of this period (post-high flux), at the beginning of period B (pre-low flux) and at the end of this period (post-low flux). The following laboratory tests were performed on each of the blood samples obtained from each study patient and once for the control subjects:

  1. Beta-2-microglobulin assay: Was done using enzyme-linked immunosorbent assay (ELISA) using a commercially available kit (DRG® Microglobulin, beta-2 EIA Kit; DRG International Inc., RUO, USA).
  2. AOPP [10] : Were measured spectrophotometrically. In 96-well microtiter plates, 200 μL serum (diluted 1:5 in phosphate-buffered saline [PBS] was acidified using 20 μL acetic acid. Absorbance of the reaction mixture was read immediately at 340 nm against a blank containing 200 μL PBS, 10 μL 1.16 mol/L potassium iodide and 20 μL acetic acid. AOPP content was determined using a standard curve constructed with chloramine-T standard solutions (Sigma-Aldrich, St. Louis, MO, USA). AOPP concentrations were expressed in μmol/L chloramine-T equivalents.
  3. PCO [19] was measured spetrophotometrically using an OxiSelect protein carbonyl spectrophotometric kit (Cell Biolabs Inc., San Diego, CA, USA). The test is based on derivitization of the PCO groups with 2,4-dinitrophenylhydrazine (DNPH). The amount of protein-hydrozone produced was measured spectrophotometrically at 375 nm. Carbonyl levels were expressed as nmoL/ mg of protein. Serum protein was assayed on the Dimension RXL chemistry auto-analyzer (Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA) and was adjusted to 1 mg/mL using distilled water. One milliliter of DNPH was added to 250 μL diluted serum. After incubation, protein was precipitated using 1.25 mL trichloracetic acid 20%. The protein pellet was washed with 1 mL ethanol/ethyl acetate (1:1 v/v) to remove any free DNPH and was solubilized in 250 μL 1M NaOH. Absorbance was read at 370 nm. Carbonyl content was calculated using a molar extinction coefficient of DNPH (22 × 10 3 / mol/cm). Because some protein may be lost during the washing steps, the protein content of the final solubilized pellet was measured by the Lowry method. [20]

   Statistical Analysis Top

Data were analyzed using STATVIEW software version 5.1 for Windows (SAS Institute Inc. Cary, NC, USA). Comparisons between patients and controls were made using the Student's t test. Changes in the studied parameters within the study patients group were analyzed using the paired t test. The Pearson's correlation test was used to investigate the relation between the studied variables. Statistical significance was considered as P-value <0.05.

   Results Top

The clinical characteristics of the study patients are depicted in [Table 1]. Hypertension was the most common cause of chronic kidney disease (30%), while the cause was not identified in 15% of the patients. All patients were dialyzed three times/week using bicarbonate dialysate. The dialysate flow rate was 500 mL/min. The duration of each session varied from 4-6 h. The blood flow rate ranged between 250 and 400 mL/min, with a mean of 323 ± 42.2 mL/min. No blood transfusion was administered to any patient during the study period.
Table 1: Characteristics of 20 patients on chronic hemodialysis.

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[Table 2] presents the baseline biochemical data of HD patients versus controls. Serum B2MG, AOPP and PCO were significantly higher in HD patients than in controls (P <0.0001).
Table 2: Baseline biochemical data and uremic toxins in HD patients versus controls.

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Significantly lower levels of serum B2MG and PCO were observed at the end of the high-flux dialysis period compared with the pre-highflux levels (P = 0.026 and 0.0005, respectively). On the other hand, no statistically significant change was observed in the AOPP levels during this period (P = 0.68) [Table 3]; the mean percent change (±standard error of the mean, SEM) in B2MG, AOPP and PCO during this period was -7.97 ± 6.84%, 1.82 ± 3.63% and -7.69 ± 5.04%, respectively [Figure 1].
Table 3: B2MG, AOPP and protein carbonyls in 20 patients before and after high-flux and low-flux HD.

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Figure 1: Mean %change in B2MG, AOPP and PCO in response to high-flux and low-flux HD. Results are shown as mean ± standard error of the mean (SEM).

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The levels of the studied parameters were comparable at the start of the high-flux period A and the low-flux period B HD, indicating the adequacy of the intervening washout period (B2MG: P = 0.311, AOPP: P = 0.66, PCO: P = 0.412).

Significantly higher levels of B2MG, AOPP and PCO were observed at the end of the eight weeks of low-flux HD compared with their levels at the beginning of this period (P = 0.0002, 0.021 and <0.0001, respectively) [Table 3]. The mean %change (±SEM) during period B for B2MG, AOPP and PCO was: 30.31 ± 6.43%, 9.13 ± 3.27% and 31.03 ± 5.05%, respectively [Figure 1].

Post-low-flux levels of B2MG and PCOs were significantly higher than the post-high-flux levels (P <0.0001). On the other hand, no significant difference was observed in the AOPP levels (P = 0.11). No significant change was observed in the serum urea levels after high-flux (P = 0.41) or low-flux HD (P = 0.57).

During the period of high-flux HD, the mean of the weekly doses of human recombinant erythropoietin required to maintain hemoglobin within the target level of 11-12 g/dL was significantly lower than the mean of the doses required during the low-flux period (3291 ± 2015 IU vs 4567 ± 2350 IU, respectively, P = 0.0062).

At baseline, a positive correlation was observed between the pre-high flux PCO and AOPP levels (r = 0.569, P = 0.007). The PCO levels also cor-related with the B2MG levels (r = 0.605, P = 0.003). At the end of period A, the post-high-flux PCO levels positively correlated with the B2MG levels (r = 0.523, P = 0.016). In addition, a significantly positive correlation was found between the pre-low-flux B2MG levels and the mean of the weekly erythropoietin doses during the low-flux HD period (r = 0.588, P = 0.011). No other correlations were detected between the studied parameters.

   Discussion Top

Recent clinical studies suggest that enhancing the removal of the middle molecules compounds has a beneficial effect on the survival and the quality of life of patients with endstage renal disease. This can be accomplished by using high-flux dialysis membranes with large pore sizes, by increasing the dialysis frequency or by prolonging the dialysis session. [21]

Comparable to previous reports, [22],[23] our study shows that at the start of the study, the baseline pre-dialysis serum levels of B2MG were considerably higher in chronic HD patients than in controls. Studies also proved that elevated B2MG blood levels contribute to early mortality. [6],[24],[25]

In the present study, serum B2MG levels showed a significant decrease after eight weeks on HD using high-flux membranes, whereas the use of low-flux dialysis resulted in increased levels comparable to other studies. [26],[27],[28]

B2MG has been used as a marker of uremic toxins in the "middle molecule" range, in particular for the assessment of dialysis efficiency. [4] However, elevated B2MG levels are not only the result of clearance but also of inflammation, and measurement of other molecules such as AOPP and carbonyl proteins is also beneficial in this regard. [29]

In the present study, the measured levels of AOPP were higher in HD patients than in controls. The elevated levels of AOPP in uremic patients, especially those on HD therapy, have been reported previously. [7],[30] However, in our study, plasma AOPP levels could not be changed in response to eight weeks of high-flux HD, and a similar observation was reported by Ward et al. [31] In addition, Bordoni et al [32] observed that plasma carbonyl residues could be significantly reduced in patients on high-flux HD, while low-flux dialysis could not achieve lower levels of either of these two markers as shown in our study patients. The absence of an effect of high-flux HD on AOPP level may be related to the large molecular weight of AOPP molecules, which are the result of damage to the albumin as well as proteins of higher molecular weights.

In our study, patients on chronic HD had significantly higher levels of PCO than control subjects. Similar results have been reported by other investigators. [11],[14],[33],[34] Carbonyl stress has been shown to contribute to long-term complications associated with chronic renal failure and HD, such as dialysis-related amyloidosis and accelerated atherosclerosis. [35]

Carbonyl stress in HD patients may result not only from uremia but also from HD therapy. During HD, biochemical reactivity following contact of blood with the dialysis membrane and the loss of antioxidant substances may promote carbonyl formation via an increase of oxidative stress. [36],[37],[38] On the other hand, HD therapy may reduce carbonyl overload by removing low-molecular weight RCOs. Furthermore, Pavone et al [33] demonstrated that HD membranes possess the ability to adsorb and carbonylate plasma proteins, and concluded that HD membranes may affect the carbonyl balance in chronic uremic patients. In the present study, serum PCO was significantly reduced at the end of the high-flux HD period, while the levels significantly increased by the end of the low-flux HD period. The molecular weights of the carbonylated proteins are much larger than the range that could be effectively removed by low-flux membranes. [33]

A positive correlation was observed in the present study between PCO content and B2MG levels both at baseline and eight weeks after high-flux HD. Miyata et al [39] demonstrated that AGE-modified B2MG binds to AGE receptors on monocytes and results in the production of cytokines and ROS, which in turn enhance tissue toxicity.

In our study, the mean of the weekly doses of rHuEpo required to maintain hemoglobin at the required target levels of 11-12 g/dL was significantly higher in the low-flux than in the high-flux HD period. In addition, the pre-low flux B2MG levels also correlated positively with the mean of the rHuEpo doses during the low-flux HD period. Several authors demonstrated that enhanced removal of uremic toxins, particularly B2MG, results in improvement of the associated anemia and the response to erythropoiesis-stimulating agents. [40],[41]

In conclusion, serum B2MG and PCOs were significantly reduced in response to high-flux HD, whereas advanced oxidation protein products were not affected. On the other hand, HD using low-flux membranes resulted in significantly increased levels of the three markers. Using high-flux HD thus allows improved removal of a wider spectrum of uremic toxins, which may improve the quality of life and reduce the morbidity and mortality in patients on chronic HD.

   References Top

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39.Miyata T, Hori O, Zhang J, et al. The receptor for advanced glycation end products (RAGE) is a central mediator of the interaction of AGE-beta 2 microglobulin with human mononuclear phagocytes via an oxidant-sensitive pathway. Implications for the pathogenesis of dialysis-related amyloidosis. J Clin Invest 1996;98:1088-94.  Back to cited text no. 39
40.Tsuchida K, Minakuchi J. Effect of large-size dialysis membrane and hemofiltration/ hemodiafiltration methods on long-term dialysis patients. Contrib Nephrol 2011;168:179-87.  Back to cited text no. 40
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Correspondence Address:
Hala S El-Wakil
Prof. of Nephrology, Faculty of Medicine, Alexandria University, Alexandria, Post Code 21411
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DOI: 10.4103/1319-2442.118082

PMID: 24029257

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