Goicoechea M, Martin J, de Sequera P, Quiroga J A, Ortiz A, Carreño V, Caramelo C
Servicio de Nefrología, Fundación Renal Iñigo Alvarez de Toledo, Universidad Autonoma de Madrid, Spain.
Kidney Int. 1998 Oct;54(4):1337-43. doi: 10.1046/j.1523-1755.1998.00084.x.
Cytokines are regulatory factors of erythropoiesis, especially in pathologic conditions. Even though a relevant role for a deranged cytokine production in the pathogenesis of dialysis anemia has been suggested, no data are available that analyze the role of cytokines in the key therapeutic issue of the needs of erythropoietin. The aim of the present study in hemodialysis patients was, therefore, to examine the relationship between the dose of recombinant human erythropoietin (EPO) and the production of cytokines by peripheral blood mononuclear cells (PBMC).
After the exclusion of subjects with major active causes of EPO resistance, data from 34 hemodialysis patients were available for analysis. Cytokine levels were measured in the supernatants of stimulated [with bacterial lipopolysaccharide and interferon gamma (IFN-gamma)] and unstimulated PBMC. Mean yearly values of hematocrit, hemoglobin, transferrin saturation, ferritin, parathormone (PTH) and aluminum levels and EPO doses (U/kg/week) were calculated. For analysis, the 34 patients were divided according to their cutoff requirements for EPO: patients with requirements of EPO > or = 60 U/kg/week (group A1, 26 subjects) versus EPO < 60 U/kg/week (group B1, 8 subjects) and patients with requirements of EPO > or = 100 U/kg/week (group A2, 18 subjects) versus <100 U/kg/week (group B2, 16 subjects).
A significant direct correlation between interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) production values and EPO doses was found (P = 0.039 and P = 0.02 respectively). On the other hand, there was a significantly negative correlation between interleukin-12 (IL-12) production values and EPO doses (P = 0.029). Patients of groups A1 and A2 had spontaneously higher tumor necrosis factor-alpha (TNF-alpha) and lower IL-12 and IFNgamma production compared to patients from groups B1 and B2.
Our data disclose a previously undescribed pattern of cytokine alteration that is relevant to determine increased needs of EPO in hemodialysis patients. The present results have potential applicability in designing strategies to improve EPO resistance.
细胞因子是红细胞生成的调节因子，尤其在病理状态下。尽管有研究提示细胞因子产生紊乱在透析性贫血发病机制中起相关作用，但尚无数据分析细胞因子在促红细胞生成素需求这一关键治疗问题中的作用。因此，本研究针对血液透析患者的目的是，探究重组人促红细胞生成素（EPO）剂量与外周血单个核细胞（PBMC）细胞因子产生之间的关系。
排除具有EPO抵抗主要活跃病因的受试者后，34例血液透析患者的数据可供分析。在经细菌脂多糖和干扰素γ（IFN-γ）刺激及未刺激的PBMC上清液中测量细胞因子水平。计算血细胞比容、血红蛋白、转铁蛋白饱和度、铁蛋白、甲状旁腺激素（PTH）和铝水平以及EPO剂量（U/kg/周）的年均值。为进行分析，根据患者对EPO的临界需求将34例患者分组：EPO需求≥60 U/kg/周的患者（A1组，26例受试者）与EPO需求<60 U/kg/周的患者（B1组，8例受试者），以及EPO需求≥100 U/kg/周的患者（A2组，18例受试者）与<100 U/kg/周的患者（B2组，16例受试者）。
发现白细胞介素-6（IL-6）和肿瘤坏死因子α（TNF-α）产生值与EPO剂量之间存在显著正相关（P分别为0.039和0.02）。另一方面，白细胞介素-12（IL-12）产生值与EPO剂量之间存在显著负相关（P = 0.029）。与B1组和B2组患者相比，A1组和A2组患者自发产生的肿瘤坏死因子-α（TNF-α）水平较高，而IL-12和IFN-γ产生水平较低。
我们的数据揭示了一种此前未描述的细胞因子改变模式，这与确定血液透析患者对EPO需求增加相关。目前的结果在设计改善EPO抵抗的策略方面具有潜在适用性。
