Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents

Abstract

<b><i>Background:</i></b> Patients with CKD frequently have anemia that results from iron-restricted erythropoiesis and inflammation. Anemia of CKD is currently managed with iron supplements and erythropoiesis-stimulating agents (ESAs) to promote erythropoiesis and with RBC transfusion in severe cases. Hyporesponse to ESAs, or the need for larger than usual doses to attain a given hemoglobin (Hb) level, is associated with increased morbidity and mortality and presents a pressing clinical challenge, particularly for patients on dialysis. This paper reviews ESA hyporesponse and potential new therapeutic options in the management of anemia of CKD. <b><i>Summary:</i></b> The most common causes of ESA hyporesponse include iron deficiency and inflammation, and to a lesser degree, secondary hyperparathyroidism, inadequate dialysis, malnutrition, and concomitant medications. Management of ESA hyporesponse is multipronged and involves treating low level infections, ensuring adequate nutrition, and optimizing iron status and dialysis modality, although some patients can remain refractory. Inflammation directly increases production and secretion of hepcidin, contributes to an impaired response to hypoxia, and suppresses proliferation of erythroid progenitors. Coordination of renal and hepatic erythropoietin (EPO) production and iron metabolism is under the control of hypoxia-inducible factors (HIF), which are in turn regulated by HIF-prolyl hydroxylases (HIF-PHs). HIF-PHs and hepcidin are therefore attractive potential drug targets particularly in patients with ESA hyporesponse. Several oral HIF-PH inhibitors have been evaluated in patients with anemia of CKD and have been shown to increase Hb and reduce hepcidin regardless of inflammation, iron status, or dialysis modality. These sustained effects are achieved through more modest increases in endogenous EPO compared with ESAs. <b><i>Key Messages:</i></b> Treatments that address ESA hyporesponse remain a significant unmet clinical need in patients with anemia of CKD. New therapies such as HIF-PH inhibitors have the potential to address fundamental aspects of ESA hyporesponse and provide a new therapeutic option in these patients.

Post-mortem liver and bone marrow iron quantification in haemodialysis patients: A prospective cohort study

“…In the sample studied, ESA hyporesponsiveness was associated with iron excess, not deficiency, as commonly thought to be the case in HD patients. 34 …”

Desidustat: First Approval

“…Renal anaemia is a common complication of chronic kidney disease (CKD), resulting from low erythropoietin (EPO) production by the failing kidney and immune activation [ 1 , 2 ]. Hypoxia-inducible factors (HIF-1α, HIF-2α and HIF-3α) are heterodimeric transcription factors that regulate cellular response to hypoxia by altering gene expression in certain cell types [ 3 , 4 ].…”

Demographic and clinical profile of black patients with chronic kidney disease attending a tertiary hospital in Johannesburg, South Africa

“…Patients with low serum bicarbonate levels were 2-fold more likely to have advanced CKD, as reported also in other studies [ 18 , 44 ]. Anaemia is common in CKD, and it is associated with decreased quality of life, high morbidity and mortality [ 48 , 49 ]. The prevalence of anaemia was 46.4% in advanced CKD, including 16.6% who had low transferrin levels, while 25.9% of the patients with early CKD had anaemia, advanced CKD was 2.9 times more prevalent if a patient had anemia and 2.4 times more prevalent if a patient had low transferrin, similar to other studies [ 20 , 21 , 50 ].…”