Locatelli Francesco, Del Vecchio Lucia, Elliott Steve
Department of Nephrology and Dialysis, Alessandro Manzoni Hospital, Lecco, Italy.
Department of Nephrology and Dialysis, Sant' Anna Hospital, ASST Lariana, Como, Italy.
Clin Kidney J. 2023 Aug 17;16(10):1563-1579. doi: 10.1093/ckj/sfad105. eCollection 2023 Oct.
The discovery and development of erythropoiesis-stimulating agents was a journey lasting more than a century, leading to the cloning and approval of recombinant human erythropoietin (rHuEpo). This was an impressive clinical advance, providing the possibility of correcting the symptoms associated with anaemia in chronic kidney disease. Associated iron use was needed to produce new haemoglobin-containing blood red cells. Partial anaemia correction became the standard of care since trials aiming for near-normal haemoglobin levels showed a higher risk of adverse cardiovascular events. Hoping to reduce the cardiovascular risks, a new category of drugs was developed and tested. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are small molecules than can be formulated into orally active pills. They simulate reduced tissue oxygen pressure, thus stimulating the production of endogenous erythropoietin (Epo) by the kidneys and liver. Clinical trials with these compounds demonstrated that HIF-PHIs are at least as effective as rHuEpo in treating or correcting anaemia in non-dialysis and dialysis patients. Trials with HIF-PHIs did not demonstrate superiority in safety outcomes and in some trials, outcomes were worse. There was also a focus on oral delivery, a possible beneficial iron-sparing effect and the ability to overcome Epo resistance in inflamed patients. A negative effect is possible iron depletion, which may explain adverse outcomes.
促红细胞生成素的发现与研发历程长达一个多世纪，最终实现了重组人促红细胞生成素（rHuEpo）的克隆与获批。这是一项令人瞩目的临床进展，为纠正慢性肾病相关贫血症状提供了可能。生成含血红蛋白的新红细胞需要补充铁。由于旨在使血红蛋白水平接近正常的试验显示心血管不良事件风险更高，部分纠正贫血成为了治疗标准。为降低心血管风险，研发并测试了一类新型药物。缺氧诱导因子脯氨酰羟化酶抑制剂（HIF-PHIs）是小分子药物，可制成口服活性药丸。它们模拟组织氧分压降低，从而刺激肾脏和肝脏产生内源性促红细胞生成素（Epo）。对这些化合物进行的临床试验表明，在治疗或纠正非透析和透析患者的贫血方面，HIF-PHIs至少与rHuEpo一样有效。HIF-PHIs试验在安全性结果方面未显示出优势，在一些试验中，结果更差。人们还关注口服给药、可能的有益铁节省效应以及克服炎症患者Epo抵抗的能力。一个负面影响可能是铁耗竭，这或许可以解释不良结果。
