Author(s):
Costa, Elísio 
; Lima, Margarida ; Rocha, Susana ; Pereira, Petronila Rocha ; Reis, Flávio ; Castro, Elisabeth ; Teixeira, Frederico ; Miranda, Vasco ; Faria, Maria do Sarmento ; Loureiro, Alfredo ; Quintanilha, Alexandre ; Belo, Luís ; Santos-Silva, Alice
Date: 2009
Persistent ID: http://hdl.handle.net/10400.14/9882
Origin: Veritati - Repositório Institucional da Universidade Católica Portuguesa
Subject(s): Resistance to recombinant human erythropoietin; Haemodialysis; Erythropoietin; Inflammation; Iron status; Leukocyte activation
Description
To better clarify the mechanism of resistance to recombinan thuman erythropoietin (rhEPO) therapy in haemodialysis patients, we studied systemic changes associated with resistance to rhEPO therapy in haemodialysis patients under rhEPO therapies, with particular interest on inflammation, leukocyte activation, iron status, oxidative stress and erythrocyte damage. We studied 63 chronic kidney disease (CKD) patients under haemodialysis and rhEPO therapies (32 responders and 31 non-responders to rhEPO therapy) and 26 healthy volunteers. In 20 of the CKD patients (10 responders and 10 non-responders to rhEPO therapy), blood samples were also collected immediately after dialysis to study the effect of the haemodialysis procedure. When compared to controls, haemodialysis patients presented
lymphopenia, which results, at least in part, from a decrease in total circulating CD3+ T-lymphocytes and affect both the CD4+ and the CD8+ T-cell subsets. These lymphocytes presented markers of enhanced continuous activation state and enhanced ability to produce Th1 related cytokines. Furthermore, haemodialysis patients presented raised markers of an inflammatory process, and of an enhanced neutrophil activation, as showed by the high serum levels of elastase. Concerning to iron status, patients showed increased ferritin and prohepcidin serum levels, and a decrease in transferrin. Furthermore, some changes were observed in erythrocyte membrane protein composition and in band 3 profile, being the decrease in spectrin the most significant change. Higher plasma levels of total antioxidant status (TAS),
lipidic peroxidation (TBA) and TBA/TAS ratio were also found. When comparing the two groups of patients, we found that non-responders presented a significant decrease in total lymphocyte and CD4+ T-cell counts, a more accentuated inflammatory process and indicators of enhanced neutrophil activation. No significant differences were found in serum iron status markers between the two groups of patients, except for the soluble transferrin receptor, which was higher among nonresponders. Prohepcidin serum levels were significantly lower in non-responders, but were higher than those in the control group.
An accentuated decrease in erythrocyte membrane spectrin, alterations in band 3 profile [decrease in band 3 proteolytic fragments (Pfrag) and in Pfrag/band 3 monomer ratio], and a trend to higher values of membrane bound haemoglobin were also found in non-responders patients.
In conclusion, although the etiology of resistance to rhEPO therapy is still unknown, our work confirms that inflammationseems to have an important role in its pathophysiology. We also showed that resistance to rhEPO therapy is associated with “functional” iron deficiency, lymphopenia and CD4+ lymphopenia, higher elastase plasma levels, increased interleukin-7 serum levels, and alterations in erythrocyte membrane protein structure and in band 3 profile. Further studies are needed to understand the rise in inflammation with the associated need in higher doses of rhEPO and the reduced iron availability.
