Iron, ESA, and HIF-Inhibitors: Are There Other Opportunities to Improve Anemia of CKD?

Anemia is a common complication of chronic kidney disease (CKD) and is associated with CKD progression and other adverse outcomes, which can result in increased rates of cardiovascular events and mortality. The search for the most effective and at the same time safe therapy for anemia in patients with CKD has always been a focus for nephrologists. The traditional treatment of CKD-dependent anemia is a combination of iron supplementation (oral and intravenous) and erythropoiesis-stimulating agents (ESA). Clinical practice data on the management of anemia in CKD patients highlight that anemia treatment is still suboptimal, and treatment is frequently omitted or underused due to a high rate of therapeutic inertia in initiating and increasing doses of anemia drugs. Moreover, ESA therapy has been associated with a risk of cardiovascular events, particularly in hypo responder patients requiring high doses or at high Hb targets. More recently, a class of oral drugs (hypoxia-inducible factor prolyl hydroxylase inhibitors) has been developed based on the modulation of the mechanisms underlying HIF oxygen sensing, leading to a simultaneous stimulation of endogenous erythropoietin production and improved iron metabolism. Unexpectedly, they went from a theoretical physiological superiority to a substantial non-inferiority, and remain largely underused likely because of the questionable concerns of their long-term safety. The landscape of the management of CKD anemia is evolving, including potential therapeutic erythropoietic strategies that are available in clinical practice and new approaches under clinical development, which can be employed as standalone approaches or eventually combined with conventional anemia treatments. We review here the most recent developments in investigational strategies for increasing erythropoiesis and improving the management of CKD anemia.