Tarng D C, Wei Y H, Huang T P, Kuo B I, Yang W C
Institute of Clinical Medicine, Department of Biochemistry, National Yang-Ming University, Taipei, Taiwan.
Kidney Int. 1999 Jun;55(6):2477-86. doi: 10.1046/j.1523-1755.1999.00479.x.
Inadequate iron mobilization and defective iron utilization may cause recombinant erythropoietin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. We have demonstrated that intravenous ascorbic acid (IVAA), but not intravenous iron medication, can effectively circumvent the functional iron-deficient erythropoiesis associated with iron overload in HD patients. However, it is uncertain whether all HD patients with hyperferritinemia will consistently respond to IVAA and which index may indicate functional iron deficiency in the special entity. Therefore, a prospective study was conducted to establish the guidelines for IVAA adjuvant therapy.
Sixty-five HD patients with serum ferritin levels of more than 500 microgram/liter were recruited and divided into the control (N = 19) and IVAA (N = 46) groups. IVAA patients with a hematocrit (Hct) of less than 30% received 300 mg of ascorbic acid three times per week for eight weeks. Controls had a Hct of more than 30% and did not receive the adjuvant therapy. Red blood cell and reticulocyte counts, iron metabolism indices, erythrocyte zinc protoporphyrin (E-ZPP), and the concentrations of plasma ascorbate and oxalate were examined before and following the therapy.
Thirteen patients (four controls and nine IVAA patients) withdrew by the end of the study. Eighteen patients had a dramatic response to IVAA with a significant increase in their hemoglobin and reticulocyte index and a concomitant 24% reduction in rEPO dose after eight weeks. This paralleled a significant rise in serum iron and transferrin saturation (TS) and a fall in E-ZPP and serum ferritin (baselines vs. 8 weeks, serum iron 68 +/- 37 vs. 124 +/- 64 microgram/dl, TS 27 +/- 10 vs. 48 +/- 19%, E-ZPP 123 +/- 44 vs. 70 +/- 13 micromol/mol heme, and serum ferritin 816 +/- 435 vs. 587 +/- 323 microgram/liter, P < 0. 05). Compared with responders, mean values of hemoglobin, rEPO dose, iron metabolism parameters, and E-ZPP showed no significant changes in controls (N = 15) and in non-responders (N = 19). Thirty-seven patients (18 responders and 19 non-responders) were further analyzed by receiver operating characteristic curves to seek the criteria for prediction of a response to IVAA treatment. The results showed that E-ZPP at a cut-off level of more than 105 micromol/mol heme and TS at a level of less than 25% were more specific to confirm the status of functional iron deficiency in iron-overloaded patients. The two criterion values had the highest accuracy to predict a response to treatment.
Functional iron-deficient erythropoiesis plays a role in rEPO-hyporesponsive anemia in HD patients with hyperferritinemia. IVAA may be an adjuvant therapy for rEPO in these patients, and E-ZPP of more than 105 micromol/mol heme and TS of less than 25% should be used to guide the IVAA treatment.
铁动员不足和铁利用缺陷可能导致铁过载的血液透析（HD）患者出现重组促红细胞生成素（rEPO）低反应性。我们已经证明，静脉注射维生素C（IVAA）而非静脉补铁药物能够有效规避HD患者中与铁过载相关的功能性缺铁性红细胞生成。然而，尚不确定所有高铁蛋白血症的HD患者是否都能持续对IVAA产生反应，以及在这一特殊群体中哪些指标可能提示功能性缺铁。因此，开展了一项前瞻性研究以制定IVAA辅助治疗的指南。
招募65例血清铁蛋白水平超过500微克/升的HD患者，分为对照组（N = 19）和IVAA组（N = 46）。血细胞比容（Hct）低于30%的IVAA组患者每周接受3次300毫克维生素C治疗，共8周。对照组Hct高于30%，未接受辅助治疗。在治疗前后检测红细胞和网织红细胞计数以及铁代谢指标、红细胞锌原卟啉（E-ZPP），并检测血浆维生素C和草酸盐浓度。
到研究结束时，有13例患者（4例对照组患者和9例IVAA组患者）退出。18例患者对IVAA有显著反应，8周后血红蛋白和网织红细胞指数显著升高，同时rEPO剂量降低24%。这与血清铁和转铁蛋白饱和度（TS）显著升高以及E-ZPP和血清铁蛋白降低相平行（基线值与8周时相比，血清铁68±37与124±64微克/分升，TS 27±10与48±19%，E-ZPP 123±44与70±13微摩尔/摩尔血红素，血清铁蛋白816±435与587±323微克/升，P<0.05）。与有反应者相比，对照组（N = 15）和无反应者（N = 19）的血红蛋白、rEPO剂量、铁代谢参数和E-ZPP的平均值无显著变化。通过绘制受试者工作特征曲线对37例患者（18例有反应者和19例无反应者）进行进一步分析，以寻找预测IVAA治疗反应的标准。结果显示，E-ZPP临界值超过105微摩尔/摩尔血红素以及TS水平低于25%对于确认铁过载患者的功能性缺铁状态更具特异性。这两个标准值对预测治疗反应具有最高的准确性。
功能性缺铁性红细胞生成在高铁蛋白血症的HD患者rEPO低反应性贫血中起作用。IVAA可能是这些患者rEPO的辅助治疗方法，应使用E-ZPP超过105微摩尔/摩尔血红素和TS低于25%来指导IVAA治疗。
