Packer Milton
Baylor Heart and Vascular Institute, Dallas, Texas, USA.
Imperial College, London, UK.
Am J Nephrol. 2024;55(2):255-259. doi: 10.1159/000531084. Epub 2023 May 16.
Renal anemia is treated with erythropoiesis-stimulating agents (ESAs), even though epoetin alfa and darbepoetin increase the risk of cardiovascular death and thromboembolic events, including stroke. Hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitors have been developed as an alternative to ESAs, producing comparable increases in hemoglobin. However, in advanced chronic kidney disease, HIF-PHD inhibitors can increase the risk of cardiovascular death, heart failure, and thrombotic events to a greater extent than that with ESAs, indicating that there is a compelling need for safer alternatives. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major cardiovascular events, and they increase hemoglobin, an effect that is related to an increase in erythropoietin and an expansion in red blood cell mass. SGLT2 inhibitors increase hemoglobin by ≈0.6-0.7 g/dL, resulting in the alleviation of anemia in many patients. The magnitude of this effect is comparable to that seen with low-to-medium doses of HIF-PHD inhibitors, and it is apparent even in advanced chronic kidney disease. Interestingly, HIF-PHD inhibitors act by interfering with the prolyl hydroxylases that degrade both HIF-1α and HIF-2α, thus enhancing both isoforms. However, HIF-2α is the physiological stimulus to the production of erythropoietin, and upregulation of HIF-1α may be an unnecessary ancillary property of HIF-PHD inhibitors, which may have adverse cardiac and vascular consequences. In contrast, SGLT2 inhibitors act to selectively increase HIF-2α, while downregulating HIF-1α, a distinctive profile that may contribute to their cardiorenal benefits. Intriguingly, for both HIF-PHD and SGLT2 inhibitors, the liver is likely to be an important site of increased erythropoietin production, recapitulating the fetal phenotype. These observations suggest that the use of SGLT2 inhibitors should be seriously evaluated as a therapeutic approach to treat renal anemia, yielding less cardiovascular risk than other therapeutic options.
肾性贫血采用促红细胞生成剂（ESAs）进行治疗，尽管阿法依泊汀和达比泊汀会增加心血管死亡和血栓栓塞事件（包括中风）的风险。缺氧诱导因子脯氨酰羟化酶结构域（HIF-PHD）抑制剂已被开发出来作为ESAs的替代药物，可使血红蛋白产生类似程度的升高。然而，在晚期慢性肾脏病中，HIF-PHD抑制剂相比ESAs会更大程度地增加心血管死亡、心力衰竭和血栓形成事件的风险，这表明迫切需要更安全的替代药物。钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可降低主要心血管事件的风险，并且它们能升高血红蛋白，这种作用与促红细胞生成素增加以及红细胞量扩充有关。SGLT2抑制剂可使血红蛋白升高约0.6 - 0.7 g/dL，从而使许多患者的贫血得到缓解。这种作用的程度与低至中等剂量的HIF-PHD抑制剂相当，甚至在晚期慢性肾脏病中也很明显。有趣的是，HIF-PHD抑制剂通过干扰降解HIF-1α和HIF-2α的脯氨酰羟化酶起作用，从而增强这两种异构体。然而，HIF-2α是促红细胞生成素产生的生理刺激因素，HIF-1α的上调可能是HIF-PHD抑制剂不必要的附属特性，这可能会产生不良的心脏和血管后果。相比之下，SGLT2抑制剂的作用是选择性增加HIF-2α，同时下调HIF-!α，这一独特特征可能有助于其心脏和肾脏方面的益处。有趣的是，对于HIF-PHD抑制剂和SGLT2抑制剂而言，肝脏可能是促红细胞生成素产生增加的重要部位，重现了胎儿期的表型。这些观察结果表明，应认真评估将SGLT2抑制剂作为治疗肾性贫血的一种治疗方法，其产生的心血管风险低于其他治疗选择。
