Pattern of resistance to erythropoietin-stimulating agents in chronic kidney disease

Abstract

Routine administration of erythropoietin (EPO)-stimulating agents (ESAs) for the control of anemia has improved the quality of life of subjects with chronic kidney disease (CKD). However, a wide variation in individual response to ESA is often observed. The reasons for EPO resistance include demographic variables such as age and gender distribution, morbidity pattern, and modality of dialysis. Despite suggestions by observational data, there is no biological characteristic that puts children at a disadvantage for adequate response to ESA. On the contrary, children possess a superior capacity for red cell production, including extramedullary erythropoiesis. The reasons for larger requirement of ESA in children (than in adults) are greater inflammatory burden, disproportionate blood loss, and greater EPO dosing by pediatric physicians. To minimize the harmful (including fatal) consequences of EPO resistance, surveillance programs must replenish nutrient (for example, iron and folate) stores, minimize oxidative hemolysis, control hyperparathyroidism, avoid catheter infection, and optimize uremic clearance. This clinical approach is justified by the inadequacy of laboratory diagnosis of pertinent etiological factors. Indeed, the best proof for functional nutrient deficiency is often a therapeutic trial. Finally, there are upcoming therapeutic agents that exploit the capacity for an endogenous EPO synthesis in CKD subjects, and may therefore minimize the off-target effect of excess dosages.

Human pluripotent stem cell–derived erythropoietin-producing cells ameliorate renal anemia in mice

“…However, although rhEPO is relatively safe, the requirement for infusions 1-3 times/week makes it difficult to return to physiological control of red blood cell production (3). In addition, the total cost of rhEPO is increasing due to the increasing number of CKD patients, and patients with anemia secondary to chronic diseases may not respond well to rhEPO (4). Finally, very rare cases of severe anemia caused by germline mutations in EPO (5) or by anti-rhEPO autoantibodies following the administration of rhEPO have also been reported (6,7).…”

Treatment of erythropoietin deficiency in mice with systemically administered siRNA

“…1,2 Some patients also become refractory to recombinant erythropoietin over time because of a variety of host factors, including Abs against the recombinant protein itself or altered iron homeostasis secondary to humoral factors such as hepcidin. 3,4 Transcription of the erythropoietin gene (EPO) is controlled by the heterodimeric transcription factor hypoxia-inducible factor (HIF) and is therefore intimately linked to oxygen delivery to the kidneys, which are normally borderline hypoxic at rest and poised to respond to further decrements in oxygen delivery. 5 HIF consists of an unstable ␣-subunit (eg, HIF1␣ or HIF2␣) and a stable ␤-subunit (eg, HIF1␤, which is also called ARNT1).…”

Prevalence and predictors of the sub-target Hb level in children on dialysis

“…Therefore, we cannot exclude the possibility of relative under dosing of ESA, as recent studies have suggested that children need absolute ESA doses similar to those used in adults [38,39]. This interpretation is likely because (i) it is common practice to dose ESA according to body weight, (ii) low Hb was observed more frequently in young children and (iii) ferritin levels did not explain the absolute Hb levels as discussed earlier.…”