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- Resistance to recombinant human erythropoietin therapy in haemodialysis patientsPublication . 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, AliceTo 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.
- Effect of aging in the perception of health-related quality of life in end-stage renal disease patients under online-hemodiafiltrationPublication . Moura, Alexandra; Madureira, José; Alija, Pablo; Fernandes, João Carlos; Oliveira, José Gerardo; Lopez, Martin; Filgueiras, Madalena; Amado, Leonilde; Sameiro-Faria, Maria; Miranda, Vasco; Santos-Silva, Alice; Costa, ElísioThis work aimed to evaluate how aging could influence patients' perception of health quality of life (HRQOL), as well as, the effect of aging on dialysis adequacy and in hematological, iron status, inflammatory and nutritional markers. In this transversal study were enrolled 305 ESRD patients under online-hemodiafiltration (OL-HDF) (59.67% males; 64.9 ± 14.3 years old). Data about comorbidities, hematological data, iron status, dialysis adequacy, nutritional and inflammatory markers were collected from patient's records. Moreover, HRQOL score, by using the Kidney Disease Quality of Life-Short Form (KDQOL-SF), was assessed. Analyzing the results according to quartiles of age, significant differences were found for some parameters evaluated by the KDQOL-SF instrument, namely for work status, physical functioning and role-physical, which decreased with increasing age. We also found a higher proportion of diabetic patients, a decrease in creatinine, iron, albumin serum levels, transferrin saturation and nPCR, with increasing age. Moreover, significant negative correlations were found between age and mean cell hemoglobin concentration, iron, transferrin saturation, albumin, nPCR, work status, physical functioning and role-physical. In conclusion, our results showed that aging is associated with a decreased work status, physical functioning and role-physical, with a decreased dialysis adequacy, iron availability and nutritional status, and with an increased proportion of diabetic patients and of patients using central venous catheter, as the vascular access. The knowledge of these changes associated with aging, which have impact in the quality of life of the patients, could be useful in their management.
- Cross-talk between inflammation, coagulation/fibrinolysis and vascular access in hemodialysis patientsPublication . Costa, Elísio; Rocha, Susana; Rocha-Pereira, Petronila; Castro, E.; Reis, Flávio; Teixeira, Frederico; Miranda, Vasco; Faria, Maria do Sameiro; Loureiro, Alfredo; Quintanilha, Alexandre; Belo, Luís; Santos-Silva, AliceThis work aimed to study the association between fibrinolytic/endothelial cell function and inflammatory markers in chronic kidney disease (CKD) patients undergoing hemodialysis (HD) and recombinant human erythropoietin (rhEPO) therapies, and its relationship with the type of vascular access (VA) used for the HD procedure. As fibrinolytic/endothelial cell function markers we evaluated plasminogen activator inhibitor type-1 (PAI-1), tissue plasminogen activator (tPA) and D-dimers, and as inflammatory markers; C-reactive protein (CRP), soluble interleukin (IL)-2 receptor (s-IL2R), IL-6 and serum albumin levels. The study was performed in 50 CKD patients undergoing regular HD, 11 with a central venous dialysis catheter (CVC) and 39 with an arteriovenous fistula (AVF), and in 25 healthy controls. Compared to controls, CKD patients presented with significantly higher levels of CRP, s-IL2R, IL-6 and D-dimers, and significantly lower levels of PAI-1. The tPA/PAI-1 ratio was significantly higher in CKD patients. We also found statistical significant correlations in CKD patients between D-dimers levels and inflammatory markers: CRP, albumin, s-IL2R and IL-6. When comparing the two groups of CKD patients, we found that those with a CVC presented statistically significant lower levels of hemoglobin concentration and albumin, and higher levels of CRP, IL-6, D-dimers and tPA. Our results showed an association between fibrinolytic/endothelial cell function and increased inflammatory markers in CKD patients. The increased levels of Ddimer, tPA and inflammatory markers in CKD patients using a CVC, led us to propose a relationship between the type of VA chosen for HD, and the risk of thrombogenesis.
- Neutrophil and monocyte activation in chronic kidney disease patients under hemodialysis and its relationship with resistance to recombinant human erythropoietin and to the hemodialysis procedurePublication . Pereira, Rui; Costa, Elísio; Gonçalves, Marta; Miranda, Vasco; Faria, Maria do Sameiro; Quintanilha, Alexandre; Belo, Luís; Lima, Margarida; Santos-Silva, AliceThe aim of the present work was to further clarify leukocyte activation due to hemodialysis (HD) procedures and to investigate its relationship with recombinant human erythropoietin resistance. Therefore, we studied the expression of CXCR1 and CD11b on neutrophils, as well as the monocyte expression of CD11b, HLA-DR, and CD14. We studied 34 chronic kidney disease (CKD) patients under HD and recombinant human erythropoietin treatment (26 responders and 8 nonresponders to recombinant human erythropoietin therapy). All CKD patients' blood samples were collected before and immediately after the HD procedure. Eighteen healthy individuals (blood donors) were also studied as a control group. Hematological data, neutrophil (CD11b and CXCR1), and monocyte (CD11b, HLA-DR, and CD14) cell surface markers were measured in all patients (before and after the HD procedure) and controls. When compared with the controls, CKD patients presented a significant decrease in CXCR1 neutrophil expression, and in CD14 monocyte expression, accompanied by a significant increase in HLA-DR monocyte expression. When comparing the 2 groups of patients, we found that nonresponders showed an additional decrease in CXCR1 neutrophil expression. After the HD procedure, a statistically significant increase in CD14 and CD11b monocyte surface markers and a decrease in CXCR1 neutrophil expression and in HLA-DR monocyte expression was found. These data further strengthen our previous studies, showing that neutrophils and monocytes are activated in CKD patients, particularly in nonresponder patients. Moreover, this activation is due, at least in part, to the HD procedure, although we should not exclude that it can also be due to the enhanced inflammatory process observed in nonresponder patients.