Anemia of chronic kidney disease: novel physiological approaches to therapy based on simulation of hypoxic response

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Abstract

Anemia is a modifiable risk factor for the progression of chronic kidney disease (CKD) and is characterized by a  decrease in the hemoglobin level, the hematocrit, and the number of circulating red blood cells. In the pre-erythropoietin era blood transfusion was a  common practice for the adequate correction of anemia in patients with CKD. However, a  recombinant human erythropoietin, that was developed and implemented into a clinical practice three decades ago, made a revolution in the renal anemia treatment. Today the management of anemia is based on the use of exogenous erythropoiesis-stimulating agents, such as erythropoietin and its analogues, as well as an oral or parenteral administration of iron. Nevertheless, despite of the high efficacy in the majority of patients this approach has a  negative side. The hemoglobin excursions, increased risk of cardiovascular complications, as well as the development of iron deficiency and chronic inflammation become additional factors in the pathogenesis of anemia associated with the renal failure. In this regard, the development of effective and safe methods of anemia management in CKD is of immediate interest. New medications based mainly on physiological approach are developed. A pharmacological activation of hypoxia-inducible factor (HIF) response is one of them. HIF is the main hormonal regulator of erythropoiesis that stimulates the production of endogenous erythropoietin. It is known that in patients with renal failure, the activation of this factor in response to hypoxia is compromised, resulting in a lack of erythropoietin production. This review covers the new mechanistic views on the hypoxic regulation of erythropoiesis and the production of erythropoietin by the kidneys, and presents the newly discovered interactions between the synthesis of erythropoietin, iron metabolism, and the chronic inflammation. Besides that, ongoing clinical trials of pharmacological HIF activators, such as FG-4592, GSK1278863, AKB-6548, BAY85-3934 are also discussed as a  new comprehensive and physiological approach for the treatment of anemia associated with CKD. Preliminary results of the clinical trials demonstrated a high efficiency of HIF activators in the treatment of renal anemia including a high tolerability, an increase in hemoglobin level and its maintenance in the target range, an increase in general capacity for iron binding and a reduction in the serum levels of both ferritin and hepcidin. However, there are some safety-related problems that include proangiogenic and adverse cardiovascular and metabolic complications, so the possibility of their development should be thoroughly studied in long-term clinical trials. 

About the authors

K. A. Aitbaev

Scientific and Research Institute of Molecular Biology and Medicine

Email: fake@neicon.ru

MD, Professor

3 Togolok Moldo str., Bishkek, 720040

Киргизия

I. T. Murkamilov

Kyrgyz State Medical Academy named after I.K. Akhunbaev

Author for correspondence.
Email: murkamilov.i@mail.ru

PhD, Nephrologist, Assistant, Chair of Faculty Therapy named after M.E. Volsky – M.M. Mirrahimova

Tel.: 0312 620991, 0557 221983

92 Akhunbaev str., Bishkek, 720020

Киргизия

V. V. Fomin

I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation

Email: fake@neicon.ru

MD, PhD, Professor, Corr. Member of Russ. Acad. Sci., Head of Chair of Faculty Therapy No. 1, Director of the Clinic of Faculty Therapy named after V.N. Vinogradov

8/2 Trubetskaya ul., Moscow, 119991

Россия

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