Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines

被引:211
作者
Macdougall, IC
Cooper, AC
机构
[1] Kings Coll London Hosp, Renal Unit, Dept Renal Med, London SE22 8PT, England
[2] Kings Coll London Hosp, Renal Unit, Dept Immunol, London SE22 8PT, England
关键词
anaemia; anti-cytokine therapy; chronic inflammation; drug resistance; recombinant human erythropoietin; uraemia;
D O I
10.1093/ndt/17.suppl_11.39
中图分类号
R3 [基础医学]; R4 [临床医学];
学科分类号
1001 ; 1002 ; 100602 ;
摘要
Up to 10% of patients with renal disease receiving recombinant human erythropoietin (rHuEPO) therapy show poor responsiveness to the drug. Even in patients who do respond to rHuEPO, there is a marked variability in drug sensitivity. Several factors have been recognized as causing resistance to rHuEPO, notably iron deficiency, infection/inflammation, and underdialysis. However, when these factors are excluded, the wide variation in responsiveness to rHuEPO persists. The mechanism of this effect needs to be fully elucidated. One hypothesis is that patients with uraemia showing resistance to rHuEPO may have enhanced levels of immune activation, causing increased release of pro-inflammatory cytokines in the bone marrow. Uraemia is known to be a chronic inflammatory state, with some patients showing considerably increased laboratory markers of inflammation and immune activation. Chronic inflammation can modify the process of erythropoiesis, probably mediated via pro-inflammatory cytokines such as interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). The concept that rHuEPO resistance is due to enhanced levels of immune activity has been investigated by studying T-cell phenotypes using flow cytometry, as well as cytokine release from T cells and monocytes in 'good' and 'poor' responders to rHuEPO. Poor responders had significantly reduced CD28 expression on both CD4+ and CD8+ cells, enhanced IL-10 generation from peripheral blood mononuclear cells (PBMCs), higher plasma IL-12 levels, and increased TNF-alpha and IFN-gamma release from PBMCs. Anti-cytokine antibodies may be useful for studying inflammatory cytokine secretion from T cells in patients with renal failure. Strategies utilizing anti-cytokine therapy may prove to be a useful adjuvant in optimizing the response to rHuEPO therapy.
引用
收藏
页码:39 / 43
页数:5
相关论文
共 15 条
[1]  
Allen DA, 1999, J INVEST MED, V47, P204
[2]  
Bergström J, 2000, SEMIN DIALYSIS, V13, P163, DOI 10.1046/j.1525-139x.2000.00044.x
[3]   Fas ligand is present in human erythroid colony-forming cells and interacts with Fas induced by interferon γ to produce erythroid cell apoptosis [J].
Dai, CH ;
Price, JO ;
Brunner, T ;
Krantz, SB .
BLOOD, 1998, 91 (04) :1235-1242
[4]   RHUEPO HYPORESPONSIVENESS - WHO AND WHY [J].
DANIELSON, B .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 1995, 10 :69-73
[5]  
DRUEKE TB, 1995, NEPHROL DIAL TRANSPL, V10, pS62
[6]  
Fishbane S, 2000, DIALYSIS TRANSPLANT, V29, P545
[7]   The interleukin-12/interleukin-12-receptor system: Role in normal and pathologic immune responses [J].
Gately, MK ;
Renzetti, LM ;
Magram, J ;
Stern, AS ;
Adorini, L ;
Gubler, U ;
Presky, DH .
ANNUAL REVIEW OF IMMUNOLOGY, 1998, 16 :495-521
[8]   European Best Practice Guidelines 14-16 -: Inadequate response to epoetin [J].
Hörl, WH ;
Jacobs, C ;
Macdougall, IC ;
Valderrábano, F ;
Parrondo, I ;
Thompson, K ;
Carveth, BG .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 2000, 15 :43-50
[9]   Immunologic function and survival in hemodialysis patients [J].
Kimmel, PL ;
Phillips, TM ;
Simmens, SJ ;
Peterson, RA ;
Weihs, KL ;
Alleyne, S ;
Cruz, I ;
Yanovski, JA ;
Veis, JH .
KIDNEY INTERNATIONAL, 1998, 54 (01) :236-244
[10]   The inflammatory response and epoetin sensitivity [J].
Macdougall, IAC ;
Cooper, A .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 2002, 17 :48-52