Is haemodiafiltration more favourable than haemodialysis for treatment of renal anaemia?

The introduction of recombinant human erythropoietin (rHuEPO) into clinical practice in the 1980s and the later new modified erythropoiesis stimulating agents (ESAs) was a real breakthrough in the treatment of severe anaemia in patients with chronic kidney disease (CKD). Use of ESAs is primarily based on an assumption that failing kidneys produce less erythropoietin which is needed for adequate erythropoiesis. However, with the development of our knowledge, the pathogenesis of anaemia in CKD becomes more and more complex (insufficient iron storage, inflammation, vitamin B12 and folic acid depletion, bone marrow fibrosis due to severe secondary hyperparathyroidism, use of myelosuppressive agents, blood loss or haemolysis, etc.). Moreover, large clinical trials failed to provide evidence that trying to achieve higher haemoglobin levels (as in subjects with normal kidney function) using ESAs is beneficial for these patients. In fact, there is a suggestion that it may be, in some cases, even harmful. Therefore current guidelines recommend haemoglobin target levels way below normal values [1]. It is reasonable to use ESA therapy in CKD patients generally to maintain Hb values ranging between 10 and 12 g/dL individualizing the value in this target range according to the possible comorbidities of the patients [2]. One of the problems we must face when treating CKD patients with ESAs is resistance to this class of medication. There are several reasons why the patient does not respond well to ESA therapy. Active blood loss, insufficient iron supply, inflammation, malnutrition and inadequate renal replacement therapy are all causes of insufficient ESA responsiveness. There is no universal definition of ESA hyporesponsiveness. According to Kidney Disease Improving Global Outcomes (KDIGO) guidelines, ESA hyporesponsiveness may be ‘initial’ (if there is no increase in Hb concentration from baseline after the first month of ESA treatment on appropriate weight-based dosing) or ‘subsequent’ (if there is need for two increases in ESA doses up to 50% beyond the dose at which the patient had been stable in order to maintain a stable Hb level) [1]. Resistance to ESA therapy correlates with worse survival in CKD patients [3–5]. Some strategies have been proposed to improve ESA responsiveness. Some new methods of therapy like intestinal adsorption of uraemic toxins with AST-120 [6], pentoxifylline [7] and vitamin D [8] have been showing promising results. Panichi et al. [9] show, in a small cross-over, randomized, multicentre study, that high-volume on-line hemodiafiltration (HV-OL-HDF) improves responsiveness to ESAs when compared with standard low-flux haemodialysis (BHD). Improved responsiveness to ESAs was accompanied by lower hepcidin concentration in a population of patients without increased inflammation markers. Hepcidin is one of the main regulators of iron homeostasis [10]. It is eliminated by the kidneys and accumulates in patients with CKD. Hepcidin binds to ferroportin, the main cellular iron efflux channel, causing its internalization and degradation. Subsequently, iron is sequestrated in macrophages and prevented from being absorbed from the intestine. A strategy aimed to lower high hepcidin levels seems to be reasonable for anaemia treatment in CKD patients. High-volume OL-HDF certainly has the potential to lower hepcidin levels. Further studies are needed, however, to determine whether it is directly eliminated through the high-flux membranes. Hepcidin is a 25-aminoacid peptide most probably not removed by low-flux BHD but potentially removable by HV-OL-HDF. ESA resistance is correlated with worse survival. It is not clear whether this association is due to some unfavourable effects of ESAs itself or rather if ESA resistance is a marker of