The evolving science of anemia management in chronic kidney disease

The articles in this edition of Kidney International Supplements timely focus on the rapidly evolving field of anemia management in patients with chronic kidney disease (CKD). The revolutionary introduction of recombinant human erythropoietin into the therapeutic arena in the 1980s profoundly changed the quality of life of most patients with end-stage kidney disease. However, it subsequently became clear that normalization of hemoglobin by erythropoiesis-stimulating agents (ESAs) was generally more harmful than beneficial, as demonstrated by several randomized controlled trials performed at the turn of the century.1, 2, 3, 4 Therefore, partial anemia correction has become the preferred treatment option in patients with CKD.

Another important issue is the frequently observed state of absolute or functional iron deficiency requiring oral or i.v. iron supplementation. Because of poor absorption of iron from the gut due to high circulating hepcidin levels and poor gastrointestinal tolerance of most oral iron agents, the administration of i.v. iron has become routine practice in most patients with end-stage kidney disease. The recently published Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial, the first of its kind in a large-size hemodialysis patient population, provided an answer to the question whether relatively high i.v. iron sucrose doses are beneficial or harmful. The trial showed that monthly proactive administration of 400 mg i.v. iron with upper limits of serum ferritin of 700 μg/L and transferrin saturation of 40% not only decreased ESA use, but also lowered the risk of all-cause death, cardiovascular events, and infections compared with reactive low-dose i.v. iron.^5,6 Clearly, more randomized controlled trials are needed in patients with non–dialysis-dependent and dialysis-dependent CKD using different i.v. iron doses and brands in different patient populations, examining patient-centered outcomes.

The development of a novel class of agents, the hypoxia-inducible factor–prolyl hydroxylase inhibitors (HIF-PHIs), represents an interesting alternative to correcting the anemia of patients with CKD,^7,8 with several possible advantages. HIF-PHIs are administered orally, in contrast to the parenteral administration of ESAs. HIF-PHIs are associated with much lower increases in circulating erythropoietin levels than treatment with traditional ESAs. Moreover, based on experimental evidence, PHIs are predicted to improve iron status by decreasing hepatic hepcidin production and to increase transcription of genes that promote iron availability.⁹ However, clinical data on a possibly reduced need for i.v. iron supplementation as well as on global efficacy and cardiovascular safety are still too limited to allow definitive conclusions. Because HIFs regulate many genes in addition to erythropoietin, other actions could exert beneficial or harmful effects.⁹ Thus, HIF-PHIs have been reported to reduce serum triglyceride, total cholesterol, and low-density lipoprotein levels, and to reduce blood pressure in animal models of CKD, an effect not observed in human patients. They could also exert anti-inflammatory effects, provide protection from ischemic injuries, and reduce CKD progression. Whether HIF-PHIs may offer an advantage over ESAs in treating the anemia of inflamed CKD patients remains to be seen. Potential concerns regarding HIF-PHIs include risk for enhanced tumor growth, pulmonary arterial hypertension, accelerated cyst growth in patients with polycystic kidney disease, proangiogenic effects in patients with vascular retinopathies, enhancement of vascular calcification, and risk for abnormal embryonic and fetal development. Therefore, despite reassuring, progressively accumulating evidence from phase 3 trials in patients with CKD, caution must be exercised regarding the benefit-to-risk ratio of HIF-PHIs in the long run compared with that of ESAs.

The articles of the present supplement, which have been written by outstanding experts in the domain of CKD anemia, deal with these different aspects. They provide excellent updates in the field of interest, with particular focus on the novel treatment modality represented by HIF-PHIs. They allow the readers of Kidney International Supplements to gain a more complete picture of the current situation while clearly pointing out still open issues that need to be addressed.

Finally, we would like to mention that yet other new anemia treatment strategies are in the pipeline. They include inhibitors of hepcidin production or action, and therapies either already in use or under investigation in other disease states, such as interleukin-6–specific antibodies, other anti-inflammatory agents, and activin receptor ligand traps.¹⁰

Time will tell which among these exciting novel approaches of anemia treatment in CKD will turn out to occupy a lasting place in clinical practice.

Disclosure

ZAM reports having received grants for Chronic Kidney Disease–Renal Epidemiology and Information Network and other research projects from Amgen, Baxter, Fresenius Medical Care, Glaxo Smith Kline, Merck Sharp and Dohme-Chibret, Sanofi-Genzyme, Lilly, Otsuka, AstraZeneca, Vifor, and the French government, as well as fees and grants to charities from Amgen, Astellas, and Sanofi-Genzyme, outside the submitted work. TBD reports having received advisor, consultant, speaker, and/or travel fees from Akebia, Amgen, Astellas, Chugai, F. Hoffman-La Roche, FMC, Glaxo-Smith-Kline, Kyowa Hakko Kirin, and Vifor.