Association between serum hepcidin‐25 and primary resistance to erythropoiesis‐stimulating agents in chronic kidney disease: a secondary analysis of the HERO trial

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The introduction of erythropoiesis‐stimulating agents (ESA) has resulted in a substantial reduction in blood transfusion requirements in patients with chronic kidney disease (CKD).1 Unfortunately, 7–14% of all patients with end‐stage kidney disease show a suboptimal haematologic response to ESA (Hb concentration <100 g/l).2 There are several known causes of suboptimal response to ESA, including female gender, lower body mass index,4 inadequate dialysis,4 older age,5 diabetes mellitus,6 cardiovascular disease,7 inflammation8 and iron (Fe) deficiency.4 The latter suggests that anaemia of CKD not only results from deficient production of erythropoietin but also from reduced Fe absorption and availability for erythropoiesis. Reduced Fe absorption is likely the consequence of excessive production of the Fe‐regulatory hormone hepcidin,10 possibly in response to elevated interleukin‐6 (IL‐6) or other pro‐inflammatory cytokines produced in CKD.
In CKD, hepcidin‐25, −22 and −20 levels are elevated and the latter two isoforms of hepcidin increase with declining renal function.13 Hepcidin levels in CKD are likely to be influenced by a number of additional factors, especially exogenously administered ESAs and Fe therapy. Inflammation (elevated IL‐6 and IL1β), Fe therapy and relative erythropoietin deficiency will increase hepcidin levels; however, erythropoietin therapy, reduced Fe stores, hypoxia and anaemia are likely to have a negative effect on hepcidin levels.14 Interestingly, erythropoietin and Fe are both administered to treat anaemia of CKD but oppose each other's actions on hepcidin production. In a non‐randomized, non‐placebo‐controlled trial, we have previously shown that administration of pentoxifylline to anaemic patients with CKD resulted in significantly reduced serum IL‐6 levels, increased haemoglobin (Hb) levels and greater Fe mobilization.15 It is highly likely that these effects are mediated via a reduction in serum hepcidin levels. Thus, pentoxifylline might be a novel agent for improvement of Fe bioavailability or reduction of total Fe dose requirement in the therapy of anaemia complicating CKD. ESA treatment targeting high haemoglobin levels in people with CKD is associated with increased risks of stroke, vascular access thrombosis and hypertension without any reduction in cardiovascular events,16 and poor response to ESA treatment is believed to be the major driver of the observed adverse outcomes in CKD.17 Unfortunately, there are no established therapies for primary ESA‐hyporesponsive anaemia.19
The Handling Erythropoietin Resistance with Oxpentifylline (HERO) trial evaluated the effect of pentoxifylline on erythropoiesis resistance index (ERI) in patients with advanced CKD and primary ESA‐hyporesponsive anaemia.20 Its sentinel findings were that pentoxifylline safely increased haemoglobin concentration in patients with ESA‐hyporesponsive anaemia but did not significantly modify ESA resistance. In this pre‐specified secondary analysis of the HERO study, the role of hepcidin‐25 in primary resistance to ESA was evaluated.
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