Effective Oral Iron Supplement for Pre-dialysis Patients

描述(申请人提供)：贫血的发展是慢性肾功能衰竭的主要问题。透析前应用重组人促红细胞生成素(RHuEPO)对其预防和早期治疗具有重要意义。RHuEPO的有效作用需要有效铁；经常需要补充铁质；口服铁剂是首选治疗方式。在这些患者中，口服铁的可获得性差异很大；其疗效无法得到保证。我们建议开发一种非侵入性的方法来直接评估决定铁吸收的两个步骤：初始粘膜摄取(IMU)和粘膜-浆膜转移(MST)。我们的方法是基于口服含有已知数量的稳定同位素标记的58FeSO4、不可吸收的标记DyC13和视觉标记亮蓝的明胶给禁食患者，然后实验室分析视觉标记的粪便样本中58Fe-过量/Dy的比率。将这一比率归一化到已知的Dy摄入量，得到IMU。实验室对两周后采集的血液样本进行的58Fe过量分析提供了全身滞留的数据，该数据与IMU的比率为MST。我们假设，铁吸收(IMU和MST)和铁储存(如血清铁蛋白所示)之间的负相关是这些患者口服铁吸收差异很大的基础；长期摄入安全剂量的抗坏血酸和/或适当的rHuEPO治疗可以增强铁吸收。在第一阶段中，我们将通过检验以下假设来确定该方法的可行性：在透析前患者中，非血红素铁(IMU和MST)的吸收与血清铁蛋白呈负相关，在20名血清铁蛋白在临床实践预期范围内的透析前患者中。在第二阶段，我们将重点研究如何通过合理使用抗坏血酸和rHuEPO来优化铁吸收(IMU和MST)。

DESCRIPTION (provided by applicant): Development of anemia is a major problem in chronic renal failure. Its prevention/early treatment with recombinant human erythropoietin (rHuEpo) during pre-dialysis phase is important. Available iron is required for efficient action of rHuEpo; iron supplements are often needed; oral iron therapy is the preferred mode. Availability of oral iron varies widely in these patients; its efficacy cannot be ensured. We propose to develop a noninvasive method for direct assessment of the two steps that determine iron absorption: initial mucosal uptake (IMU), mucosal-serosal transfer (MST). Our approach is based on oral administration of a GelCap with known amounts of stable-isotope-labeled 58FESO4, the non-absorbable marker DyC13, and the visual marker brilliant blue to fasted patients, followed by laboratory analysis of the ratio 58Fe- Excess/Dy in the visually-marked sample of stool. Normalizing this ratio to the known intake of Dy yields IMU. Laboratory analysis of a blood sample taken two weeks later for 58Fe-Excess provides data for whole-body retention and the ratio of this to IMU is MST. We hypothesize that the inverse correlation between iron absorption (IMU and MST) and iron stores (as indicated by serum ferritin) is the basis for the widely variable absorption of oral iron in these patients; and that iron absorption can be enhanced by chronic ingestion of safe doses of ascorbic acid, and/or appropriate rHuEpo treatment. During Phase-I we will establish the feasibility of the approach by testing the following HYPOTHESIS: absorption of nonheme iron (IMU and MST) is inversely related to serumferritin in pre-dialysis patients, in 20 pre-dialysis patients with serum ferritin in the range expected in clinical practice. During Phase-II we will focus on how to optimize iron absorption (IMU and MST) by judicious administration of ascorbic acid and rHuEpo.