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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2014  |  Volume : 25  |  Issue : 1  |  Page : 73-78
Evaluation of the effect of pentoxifylline on erythropoietin-resistant anemia in hemodialysis patients


1 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
2 Nephrology Ward, Department of Internal Medicine, Imam-Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
3 Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
4 Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
5 Medical Ethics and History of Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
6 Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

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Date of Web Publication7-Jan-2014
 

   Abstract 

Use of recombinant human erythropoietin (rh-Epo) improves hemoglobin (Hgb) in 90-95% of the cases of anemia of chronic kidney disease (CKD). However, it is known that pro­inflammatory cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alfa (TNF-α) and interleukin-1 (IL-1) suppress erythropoiesis, resulting in inadequate response to rh-Epo. Pentoxifylline has been shown to have modulatory effects on the immune system. This prospec­tive study to evaluate the effect of pentoxyphylline on erythropoeisis was performed on 15 (eight males, seven females) clinically stable patients who had been on hemodialysis for at least six months with anemia (Hgb of <10.7 g/dL) unresponsive to rh-Epo despite high doses. They were treated with 400 mg pentoxifylline tablets once daily for 12 weeks. Hgb increased after one and two months of drug administration, but significant changes were observed in eight (53%) patients after three months (P <0.05). Our study illustrates a probable new use for an old medicine. Three months treatment with pentoxifylline was seen to increase Hgb significantly in rh-Epo-resistant patients. More prospective studies with a larger sample size are needed to determine the inhi­bitory role of cytokines on hematopoiesis and exploring new drugs or new drug indications to overcome anemia in advanced renal failure.

How to cite this article:
Mohammadpour AH, Nazemian F, Khaiat MH, Tafaghodi M, Salari P, Charkazi S, Naghibi M, Shamsara J. Evaluation of the effect of pentoxifylline on erythropoietin-resistant anemia in hemodialysis patients. Saudi J Kidney Dis Transpl 2014;25:73-8

How to cite this URL:
Mohammadpour AH, Nazemian F, Khaiat MH, Tafaghodi M, Salari P, Charkazi S, Naghibi M, Shamsara J. Evaluation of the effect of pentoxifylline on erythropoietin-resistant anemia in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2019 Jul 17];25:73-8. Available from: http://www.sjkdt.org/text.asp?2014/25/1/73/124492

   Introduction Top


Chronic renal failure is a progressive pro­cess and, by time, some complications of renal failure become more significant. Controlling anemia, one of the main complications, not only manages this complication of chronic re­nal failure but also decreases the rate of renal function decline or, in some cases, may even arrest the process of progression. Although this type of anemia has a multifactorial etio­logy, erythropoietin (EPO) deficiency is the major mechanism of renal anemia. The com­mon use of recombinant human erythropoietin (rh-Epo) has changed the management of ane­mia in chronic renal failure, and the hemoglo­bin (Hgb) concentration improves in 90-95% of the treated patients. Some of the erythropoiesis inhibitory factors may play a contri­butory role, which causes inadequate response to rh-Epo, and, in a subset of these, no obvious reason (such as iron deficiency) can be deter­mined. [1] The lack of response to rh-Epo may be due to increased immune function, which occurs in renal failure patients. It has been known that some proinflammatory cytokines such as interferon-gamma (IFN-γ), tumor nec­rosis factor-alfa (TNF-α) and interleukin-1 (IL-1) suppress erythropoiesis in vitro. [4],[5] For­merly, it has been shown that T cells from renal failure patients responding poorly to rh-Epo generate more IFN-γ and TNF-α com­pared with both good responders to rh-Epo and healthy controls. [6] These substances act by dif­ferent mechanisms such as shortened red cell survival, abnormal mobilization of reticulo­endothelial iron stores, blunted EPO response and impaired erythroid colony formation in response to EPO.

Pentoxifylline, a methyl xanthine derivative, is a phosphodiesterase inhibitor, was first re­cognized by its hemorrheological properties with favorable effects on microcirculatory blood flow. [9] In addition to these rheological effects, it has been shown to have modulatory effects on the immune system in the context of inflammatory states as reducing the free oxy­gen radical generation by neutrophils, [10],[11] affec­ting macrophage function. [12] Additionally, this substance suppresses the induction of TNF-α in endotoxin-treated murine macrophages. [13] Furthermore, pentoxifylline can decrease TNF-α production in healthy volunteers given endo­toxin [14],[15] as well as in renal transplant patients following the administration of OKT3 mono­clonal antibodies. [16]

There are only a few studies that have evaluated the erythrogenic effects of pentoxifylline on erythropoiesis in renal failure patients who are resistant to rh-Epo. [17] Although they ob­served positive effects, it needs to be inves­tigated further. Therefore, we evaluated the beneficial effect of pentoxifylline on anemia resistant to EPO among chronic renal failure patients.


   Materials and Methods Top


This study was performed prospectively in the Nephrology Department of Imam Reza Hospital of Mashhad University of Medical Sciences between January 2006 and Septem­ber 2006. We enrolled 15 (eight males, seven females) patients with end-stage renal disease (ESRD) glomerular filtration rate (GFR) <15 mL/min/1.73m 2 ) whose anemia was unrespon­sive to rh-Epo. Inclusion criteria was ESRD patients on hemodialysis for at least six months with anemia (Hgb of <10.7 g/dL) des­pite receiving rh-Epo at a dose of ≥12,000 IU/week. Those with secondary hyperparathy­roidism, iron deficiency anemia, aluminum toxicity, occurrence of acute infection, serum albumin more than 4 g/dL, on medications such as angiotensin-converting enzyme inhi­bitors (ACEIs), theophylline preparation and androgens were excluded. All subjects gave informed consent to participate in the study. The study was accepted by the Ethics Com­mittee of Mashhad University of Medical Science.

All patients were in a stable clinical state. The subjects were treated with 400 mg pento­xifylline film-coated tablets (Trental®) once daily for 12 weeks. Serum concentration of TNF-ot, calcium, phosphorus, parathyroid hor­mone (PTH), ferritin, iron and total iron bin­ding capacity (TIBC) were measured before treatment and eight weeks after treatment and complete blood count (CBC) (was checked at the baseline and at monthly intervals. Serum samples were collected in the morning imme­diately before a dialysis session in sterile tubes, centrifuged at 10,000 rpm for 10 min and then stored at -70 °C until the time of determination. Serum TNF-α concentration was determined using the enzyme-linked immunosorbent assay method.


   Statistical Analysis Top


Statistical analyses were carried out using SPSS software (version 11.5). Results are pre­sented as the mean ± SD. The pre- and post-treatment variables were compared by Stu­dent's paired t test and independent two sam­ples "t" test analyzed the differences between the demographic data of the patients. Correla­tion analysis was assessed by the Pearson cor­relation. Results were considered significant at P <0.05.


   Results Top


The demographic data and biochemical para­meters of 15 enrolled patients are shown in [Table 1].
Table 1: Demographic and laboratory data of patients.

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Effect of pentoxifylline on hemoglobin concen­tration

Hgb levels were measured at baseline and after one, two, and three months pentoxifylline treatment [Table 2]. Hgb increased after one and two months of drug administration, but significant changes in Hgb concentration were observed in eight patients after three months (P <0.05). Appropriate therapeutic response, defined as ≥1 g/dL increase in Hgb con­centrations after three months of treatment, was observed in 53% of the patients [Figure 1]. The others were categorized as poor responders. The dose of rhu-Epo beyond which the patient is regarded as refractory was 432 IU/kg ± 45.
Figure 1: Changes in hemoglobin concentrations in good responders during the study period.

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Table 2: Hemoglobin concentrations during study.

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Effect of pentoxifylline on TNF-α serum concentration

TNF-α serum concentration was measured at baseline and eight weeks after treatment [Table 3]. In good responders, the TNF-α serum concentration was significantly higher than that in poor responders, and it decreased sig­nificantly (P <0.05) after eight weeks; but, in poor responders, the TNF-α serum concen­tration did not change significantly [Table 4] and [Figure 2]. Mean serum TNF-α concen­trations did not change significantly after eight weeks of treatment with pentoxifylline in the whole group.
Figure 2: Changes in serum TNF-α concentration in good responders during the study period.

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Table 3: Comparison of TNF-α serum concentration at baseline and eight weeks after pentoxifylline treatment.

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Table 4: Comparison of TNF-α serum concentration at baseline and eight weeks between poor responders and good responders.

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Correlation between TNF-α serum concentra­tion and hemoglobin concentration

In good responders (eight patients), there was an inverse significant correlation between TNF-α serum concentration and Hgb level (P = 0.046, CC = -0.522). But, in seven poor responder patients, there was no correlation bet­ween the two parameters.


   Discussion Top


Our study illustrates a probable new use for an old medicine. Pentoxifylline is indicated for the treatment of peripheral vascular disease, but, still, there are only limited studies that investigated its role as adjuvant therapy to rh-Epo in hemodialysis patients. [17] Some co-exis­ting factors such as iron deficiency, hemo­dialysis, hyperparathyroidism and comorbid factors (acute infection and use of concurrent medication such as ACEIs) affect rh-Epo res­ponse as well as pentoxifylline therapeutic response. [1] We excluded all of these factors. Although it is an uncontrolled study, it was conducted under rigorous scientific conditions. The patients were carefully selected as those who had remained persistently anemic, with Hgb levels less than 10.7 g/dL despite recei­ving high doses of rh-Epo. [17] This clinical state had persisted for a minimum of six months in all patients, and indeed most of them had failed to achieve their target Hgb level for three consecutive months before pentoxifylline the­rapy and no other interventions or clinical events coincided in the study period. Therefore, it is suggested that alteration in Hgb concen­tration seen was the result of pentoxifylline treatment in patients. This study demonstrates that three months treatment with pentoxifylline can increase the Hgb concentration significantly in rh-Epo-resistant patients. The mechanism of action of pentoxifylline in this population may be diffe­rent from the other mechanisms of action. A common feature of hemodialysis patients is inflammation, which is taking into account as a major cause of morbidity and mortality, and it has been suggested that there is a well-docu­mented association between inflammation and hemodialysis. Several factors have been known as potential causes of inflammation in hemo­dialysis patients, which include contaminated dialysate, bioincompatible membranes, cytokine clearance impairment, undiagnosed persistent infections, accumulation of advanced glycation end products and reduced plasma antioxi­dant activity. [8],[18] Different studies reported that the presence of inflammation, in association with a rise in the serum level of proinflam­matory cytokines, may be the second most common cause of resistant anemia. Cooper et al evaluated the expression of Epo-inhibiting cytokines (INF-y, TNF-ot, IL-10, IL-13) by T cells in patients exhibiting poor response to Epo therapy. This study has demonstrated that T cells of anemic patients who are resistant to Epo have an anti-proliferative effect on erythroid progenitors in vitro; specifically, these cytokines inhibit the formation of erythroid colony-forming units that are the early deve­lopment precursors of red cells that proliferate in the bone marrow. [17] Formerly, Navarro et al found that pentoxifylline with its anti-cytokine properties can improve hematological status in anemic patients with advanced renal failure as evidenced by decreasing serum TNF-α con­centration and increased Hgb in pentoxifylline-treated patients. [19] Therefore, in our opinion, the increased production of these cytokines may account for rh-Epo hyporesponsiveness. This finding supports the concept of effectiveness of antagonizing the action of these proinflam­matory cytokines in treating inflammatory ane­mia. [20]

The pentoxifylline anti-inflammatory proper­ties mediate via inhibition of phosphodieste­rase, inhibition of production of TNF-α by monocytes and production of INF-γ by T cells. [17] A study on purified T cells reported that pentoxifylline reduced stimulated TNF-α , IL-5 and IL-10 production. [21] In a murine mo­del of allergic pulmonary inflammation, pento­xifylline treatment reduced INF-γ from stimu­lated spleen cells. [22] TNF-α is thought to play a central role in the pathogenesis of anemia caused by inflammation. [5],[23] Therefore, one can postulate that the beneficial effect of pentoxi­fylline on Epo-resistant anemia in this study is related to its anti-inflammatory properties, which is supported by our results in good responders who showed a rise in the Hgb con­centration in association with reduction in TNF-α serum concentration. To the best of our knowledge, there are only two clinical trials in this field. [17],[19] Our results support those studies and confirm that pentoxifylline may improve the hematologic status in uremic patients. There is still a necessity for expanded investigation as prospective studies with a large sample size to determine the inhibitory role of cytokines on hematopoiesis and exploring new drugs or new drug indications to overcome anemia in advanced renal failure.


   Conflict of interest Top


The authors declare that there is no conflict of interest in this work.

 
   References Top

1.Drueke T. Hyporesponsiveness to recombinant human erythropoietin. Nephrol Dial Transplant 2001;16 Suppl 7:25-8.  Back to cited text no. 1
    
2.Stenvinkel P. The role of inflammation in the anaemia of end-stage renal disease. Nephrol Dial Transplant 2001;16 Suppl 7:36-40.  Back to cited text no. 2
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3.Macdougall IC, Cooper A. The inflammatory response and epoetin sensitivity. Nephrol Dial Transplant 2002;17 Suppl 1:48-52.  Back to cited text no. 3
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4.Means RT Jr, Dessypris EN, Krantz SB. Inhi­bition of human erythroid colony-forming units by interleukin-1 is mediated by gamma interferon. J Cell Physiol 1992;150:59-64.  Back to cited text no. 4
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5.Allen DA, Breen C, Yaqoob MM, Macdougall IC. Inhibition of CFU-E colony formation in uremic patients with inflammatory disease: Role of IFN-gamma and TNF-alpha. J Investig Med 1999;47:204-11.  Back to cited text no. 5
    
6.Cooper AC, Mikhail A, Lethbridge MW, Kemeny DM, Macdougall IC. Increased expres­sion of erythropoiesis inhibiting cytokines (IFN-gamma, TNF-alpha, IL-10, and IL-13) by T cells in patients exhibiting a poor response to erythropoietin therapy. J Am Soc Nephrol 2003;14: 1776-84.  Back to cited text no. 6
    
7.Means RT Jr. Pathogenesis of the anemia of chronic disease: A cytokine-mediated anemia. Stem Cells 1995;13:32-7.  Back to cited text no. 7
[PUBMED]    
8.Rogiers P, Zhang H, Leeman M, et al. Erythro-poietin response is blunted in critically ill patients. Intensive Care Med 1997;23:159-62.  Back to cited text no. 8
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9.Ward A, Clissold SP. Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic pro­perties, and its therapeutic efficacy. Drugs 1987; 34:50-97.  Back to cited text no. 9
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10.Thiel M, Bardenheuer H, Poch G, Madel C, Peter K. Pentoxifylline does not act via adenosine receptors in the inhibition of the superoxide anion production of human polymorphonuclear leuko­cytes. Biochem Biophys Res Commun 1991; 180:53-8.  Back to cited text no. 10
    
11.McDonald RJ. Pentoxifylline reduces injury to isolated lungs perfused with human neutrophils. Am Rev Respir Dis 1991;144:1347-50.  Back to cited text no. 11
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12.Williams JH Jr, Heshmati S, Tamadon S, Guerra J. Inhibition of alveolar macrophages by pentoxifylline. Crit Care Med 1991;19: 1073-8.  Back to cited text no. 12
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13.Strieter RM, Remick DG, Ward PA, et al. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem Biophys Res Commun 1988; 155:1230-6.  Back to cited text no. 13
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14.Zabel P, Wolter DT, Schonharting MM, Schade UF. Oxpentifylline in endotoxaemia. Lancet 1989;2:1474-7.  Back to cited text no. 14
    
15.Waage A, Sorensen M, Stordal B. Differential effect of oxpentifylline on tumour necrosis factor and interleukin-6 production. Lancet 1990;335: 543.  Back to cited text no. 15
    
16.Alegre ML, Gastaldello K, Abramowicz D, et al. Evidence that pentoxifylline reduces anti-CD3 monoclonal antibody-induced cytokine release syndrome. Transplantation 1991;52: 674-9.  Back to cited text no. 16
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17.Cooper A, Mikhail A, Lethbridge MW, Kemeny DM, Macdougall IC. Pentoxifylline improves hemoglobin levels in patients with erythropoietin-resistant anemia in renal failure. J Am Soc Nephrol 2004;15:1877-82.  Back to cited text no. 17
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18.Roodman GD, Johnson RA, Clibon U. Tumor necrosis factor alpha and the anemia of chronic disease: Effects of chronic exposure to TNF on erythropoiesis in vivo. Adv Exp Med Biol 1989;271:185-96.  Back to cited text no. 18
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19.Navarro JF, Mora C, Garcia J, et al. Effects of pentoxifylline on the haematologic status in anaemic patients with advanced renal failure. Scand J Urol Nephrol 1999;33:121-5.  Back to cited text no. 19
    
20.Danielson B. R-HuEPO hyporesponsiveness-who and why? Nephrol Dial Transplant 1995; 10 Suppl 2:69-73.  Back to cited text no. 20
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21.Jimenez JL, Punzon C, Navarro J, Munoz-Fernandez MA, Fresno M. Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-kappaB and nuclear factor of activated T cells activation. J Pharmacol Exp Ther 2001;299: 753-9.  Back to cited text no. 21
    
22.Fleming CM, He H, Ciota A, Perkins D, Finn PW. Administration of pentoxifylline during allergen sensitization dissociates pulmonary allergic inflammation from airway hyper-responsiveness. J Immunol 2001;167:1703-11.  Back to cited text no. 22
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23.Means RT Jr. Recent developments in the anemia of chronic disease. Curr Hematol Rep 2003;2: 116-21.  Back to cited text no. 23
[PUBMED]    

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Correspondence Address:
Fatemeh Nazemian
Nephrology Ward, Department of Internal Medicine, Imam-Reza Hospital, Mashhad University of Medical Sciences, Mashhad
Iran
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DOI: 10.4103/1319-2442.124492

PMID: 24434385

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