自1800年代以来，贫血被认为是慢性肾脏疾病（CKD）的并发症。其原因是多种多样的，包括红细胞生成素缺乏症，铁缺乏症，炎症，红细胞的寿命降低，继发性甲状旁腺功能亢进和失血等。自促红细胞生成素（EPO）刺激剂（ESA）的发展以来的30年中，没有新的治疗选择。尽管与铁疗法相比undesirable side effectssuch as hypertension, increased risk of malignancy, cardiovascular and thromboembolic events, and even mortality due to off-target effects.

When oxygen levels in the kidney drop, peritubular interstitial cells in the cortico-medullary junction activate a variety of genes to adapt to the hypoxia, including those that synthesize EPO with the goal of re-establishing oxygen delivery to the kidney. One such important pathways is the hypoxia-inducible factor (HIF) pathway, discovered in 1992 byGregg Semenza and G. L. Wang，，，，which resulted in a Nobel Prize in physiology/ Medicine in 2019.

HIF is a transcription factor. In short, hypoxia leads to the stabilization of HIF via prolyl hydroxylase inhibitors (PHIs), and oxygen causes proteolysis of HIF via hydroxylation of prolyl residues. The components that stabilize HIF are called HIF stabilizers. Figure 1 summarizes the physiology of HIF and their role in erythropoiesis.

Figure 1 from Fogo et al, AJKD ©2017 Gupta & Wish

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Figure 1 fromFogo et al，，，，AJKD.©2017 Gupta & Wish

The HIF pathway operates in virtually all cells and controls the rate of transcription of hypoxia-responsive genes. In addition to assisting with erythropoiesis via gene upregulation, HIF has effects via upregulating divalent metal transporter 1 (DMT1) and duodenal cytochrome B (DcytB) to increase intestinal iron absorption, suppress hepcidin, and increase expression of erythropoietin and transferrin receptors on erythroblasts.

HIF-PHIs are orally administered anemia drugs that are approved for marketing in Japan and China and recently were approved by theEuropean commission。They are not yet approved by the FDA in the United states. This recentAJKDpaper fromWish et alsummarizes the discussions on Roxadustat, Vadadustat, and Daprodustat from a scientific workshop sponsored by the National Kidney Foundation held in 2019.

Roxadustat：

Clinical studies conducted on Roxadustat showed that it is不属于Epoetin alfa在透析患者over a 26-week treatment period, although hyperkalemia was increased in patients on roxadustat. In CKD patients not on kidney replacement therapy (KRT), Roxadustat increased hemoglobin (Hgb) by 2g/dLcompared to placebo，再次注意到高钾血症和代谢性酸中毒。在3个全球3阶段研究中，针对KRT的CKD患者（n = 4270），在平均暴露约1.62年的情况下，安慰剂组的HGB增加了HGB为1.85 g/dL VSS 0.13 g/dl。Roxadustat减少了对ESA治疗，IV铁或输血的需求。利用时间首先进行主要不良心血管事件（MACE）作为终点，治疗组没有差异。在roxadustat和安慰剂治疗的患者之间，不良事件和严重的不良事件的总体发生率相似。

Other beneficial effects observed with roxadustat, though not consistently reported, were greater decrease in hepcidin levels compared to epoetin or placebo and lowering of LDL- cholesterol.

Vadadustat:

在透析患者(2 studies , N= 3923), vadadustat vs. darbepoetin groups showed marginal mean differences in Hb levels. In the pooled analysis, MACE and adverse events were similar for vadadustat vs. darbepoetin.

在没有KRT的CKD患者中将Vadadustat与Darbepoetin进行了比较在两项研究中，HB <10 g/dL的ESA患者（n = 1751），一名在美国和9--的HB 8-11 g/dL的ESA治疗患者（n = 1725）中。美国境外12 g/dl。尽管双臂的HGB的上升相似，但由于该队列中合并的狼牙棒事件率略高，因此Vadadustat并未符合非自卑标准。

Daprodustat：

A phase 3 study randomized 271 patients on dialysis in Japan to either continuation with darbepoetin or conversion to daprodustat over 52 weeks. A rise in Hb was non-inferior and the need for IV iron was decreased in the daprodustat group. The small sample size limited the evaluation of safety, and the United States is moving through phase 3 studies.

Table 1 shows the pharmacokinetic properties of the 3 HIF-PHI drugs Daprodustat, Roxadustat and Vadadustat.

Table 1 fromWish et al，，，，AJKD.© National Kidney Foundation

Unanswered questions/ Safety issues:

Although we have several ongoing trials, the evaluation of adverse events is limited to a relatively short treatment period. The early data suggests that there is MACE non-inferiority compared to ESA in patients on dialysis, but this is less clear in patients with CKD without the need for kidney replacement therapy. Additionally, outcomes data on thrombotic events, cholesterol lowering effects, hyperkalemia, malignancy, and even aspects like pulmonary arterial hypertension and cyst growth leave more questions than answers currently. Box 1 summarizes possible safety issues and future research recommendations.

Box 1 from Wish et al, AJKD. © National Kidney Foundation

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Box 1 fromWish et al，，，，AJKD.© National Kidney Foundation

The knowledge of oxygen homeostasis pathways and its application in developing novel therapeutics in CKD is very exciting. At the same time, balancing the off-target effects of these compounds is very challenging. The ongoing studies may provide more data to ensure the efficacy and safety of these compounds, which will hopefully translate into a new tool in the management of CKD patients.

– Post prepared bySai Sudha Mannemuddhu@drM_sudha，ajkdblog客人贡献者

To viewWish et al(subscription required), please visitajkd.org。

标题：Hypoxia-Inducible Factor Stabilization as an Emerging Therapy for CKD-Related Anemia: Report From a Scientific Workshop Sponsored by the National Kidney Foundation
作者：Jay B. Wish, Kai-Uwe Eckardt, Csaba P. Kovesdy, Steven Fishbane, Bruce S. Spinowitz, Jeffrey S. Berns
DOI:10.1053/j.ajkd.2021.06.019