Neutrophil Activation and Resistance to Recombinant Human Erythropoietin Therapy in Hemodialysis Patients

Costa, Elı́sio; Rocha, Susana; Rocha‐Pereira, Petronila; Nascimento, Henrique; Castro, Elisabeth; Miranda, Vasco; Faria, Maria do Sameiro; Loureiro, Alfredo; Quintanilha, Alexandre; Belo, Luı́s; Santos-Silva, Alice

doi:10.1159/000142147

Cited by 44 publications

(51 citation statements)

References 33 publications

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“…In CKD, plasma elastase levels are elevated, [39][40][41] and primed neutrophils are associated with inflammation and oxidative stress. 28 Our findings indicate that regular exercise does not exacerbate the activation state of resting neutrophils (although transient spontaneous neutrophil activation occurs during each exercise bout).…”

Section: Effects Of Regular Exercisementioning

confidence: 99%

Evidence for Anti-Inflammatory Effects of Exercise in CKD

Viana

Kosmadakis

Watson

et al. 2014

Journal of the American Society of Nephrology

158

128

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CKD is associated with a complex state of immune dysfunction characterized by immune depression, predisposing patients to infections, and immune activation, resulting in inflammation that associates with higher risk of cardiovascular disease. Physical exercise may enhance immune function and exert antiinflammatory effects, but such effects are unclear in CKD. We investigated the separate effects of acute and regular moderate-intensity aerobic exercise on neutrophil degranulation (elastase release), activation of T lymphocytes (CD69 expression) and monocytes (CD86 and HLA-DR expression), and plasma inflammatory markers (IL-6, IL-10, soluble TNF-receptors, and C-reactive protein) in patients with predialysis CKD. A single 30-minute (acute) bout of walking induced a normal pattern of leukocyte mobilization and had no effect on T-lymphocyte and monocyte activation but improved neutrophil responsiveness to a bacterial challenge in the postexercise period. Furthermore, acute exercise induced a systemic anti-inflammatory environment, evidenced by a marked increase in plasma IL-10 levels (peaked at 1 hour postexercise), that was most likely mediated by increased plasma IL-6 levels (peaked immediately postexercise). Six months of regular walking exercise (30 min/d for 5 times/wk) exerted anti-inflammatory effects (reduction in the ratio of plasma IL-6 to IL-10 levels) and a downregulation of T-lymphocyte and monocyte activation, but it had no effect on circulating immune cell numbers or neutrophil degranulation responses. Renal function, proteinuria, and BP were also unaffected. These findings provide compelling evidence that walking exercise is safe with regard to immune and inflammatory responses and has the potential to be an effective anti-inflammatory therapy in predialysis CKD.

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Section: Effects Of Regular Exercisementioning

confidence: 99%

Evidence for Anti-Inflammatory Effects of Exercise in CKD

Viana

Kosmadakis

Watson

et al. 2014

Journal of the American Society of Nephrology

158

128

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“…There are many conditions reported as being associated with rhEPO resistance, namely, inflammation, oxidative stress, and iron deficiency (24,41). C-reactive protein (CRP), IL-6, soluble IL-2, and elastase plasma levels had been described as inflammatory markers for rhEPO responsiveness in hemodialysis patients (11,13). Iron deficiency markers include mean cell hemoglobin, red cell distribution width, and soluble transferrin receptor (s-TfR) serum levels (12).…”

Section: R776 Population Pd Modeling Of Erythropoiesis In Preterm Infmentioning

confidence: 99%

Population pharmacodynamic analysis of erythropoiesis in preterm infants for determining the anemia treatment potential of erythropoietin

Saleh

Nalbant

Widness

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Saleh MI, Nalbant D, Widness JA, Veng-Pedersen P. Population pharmacodynamic analysis of erythropoiesis in preterm infants for determining the anemia treatment potential of erythropoietin. Am J Physiol Regul Integr Comp Physiol 304: R772-R781, 2013. First published March 13, 2013 doi:10.1152/ajpregu.00173.2012.-A population pharmacokinetics/pharmacodynamic (PK/PD) model was developed to describe changes in erythropoiesis as a function of plasma erythropoietin (EPO) concentration over the first 30 days of life in preterm infants who developed severe anemia requiring red blood cell (RBC) transfusion. Several covariates were tested as possible factors influencing the responsiveness to EPO. Discarded blood samples in 27 ventilated preterm infants born at 24 -29 wk of gestation were used to construct plasma EPO, hemoglobin (Hb), and RBC concentration-time profiles. The amount of Hb removed for laboratory testing and that transfused throughout the study period were recorded. A population PK/PD model accounting for the dynamic Hb changes experienced by these infants was simultaneously fitted to plasma EPO, Hb, and RBC concentrations. A covariate analysis suggested that the erythropoietic efficacy of EPO is increased for preterm infants at later gestational ages. The PD analysis showed a sevenfold difference in maximum Hb production rate dependent on gestational age and indicated that preterm infants, when stimulated by EPO, have the capacity to produce additional Hb that may result in a decrease in RBC transfusions. The present model has utility in clinical trial simulations investigating the treatment potential of erythropoietic stimulating agents in the treatment of anemia of prematurity. erythropoiesis; preterm infants; pharmacodynamics; gestational age ANEMIA IS A FREQUENT COMPLICATION in very low birth weight (VLBW) premature infants (birth weight Ͻ1,500 g) that is usually referred to as anemia of prematurity (14). There are two main causes of anemia of prematurity: insufficient erythropoietin (EPO) production and heavy blood loss resulting from frequent laboratory blood sampling (53). Previous studies have shown that during the first 4 wk of life in preterm infants with a gestational age Ͻ28 wk or birth weights Ͻ1 kg, approximately twice the volume of red blood cells (RBCs) transfused relative to the volume removed for laboratory blood testing (50). Thus the effect of blood sampling is substantial and must be considered in the management of anemia and in the assessment of erythropoiesis in preterm infants. Anemia of prematurity is also exacerbated by other factors such as shortened RBC life span and the rapid expansion of blood volume with growth (32).For many years, RBC transfusion was the only effective treatment for severe anemia of prematurity. In 1987, the first clinical trial of EPO demonstrated that EPO treatment was demonstrated to reduce the need for RBC transfusions in adults with end-stage renal disease (18). Subsequently, there has been a series of reports demonstrating variable results regarding th...

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“…4 In previous studies performed by our group, a decrease in the number of circulating T cells was found in HD patients, both in CD4 + and in CD8 + T-cell compartments. 5,6 There are some possible explanations for T-cell depletion in HD patients, namely, higher turnover, disturbances in lymphocyte homeostasis due to uremia, and increased peripheral lymphocyte apoptosis associated with activation stimulus.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis of Peripheral CD4⁺T-Lymphocytes in End-Stage Renal Disease Patients Under Hemodialysis and rhEPO Therapies

Borges

Fernandes

et al. 2011

Renal Failure

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Neutrophil Activation and Resistance to Recombinant Human Erythropoietin Therapy in Hemodialysis Patients

Cited by 44 publications

References 33 publications

Evidence for Anti-Inflammatory Effects of Exercise in CKD

Evidence for Anti-Inflammatory Effects of Exercise in CKD

Population pharmacodynamic analysis of erythropoiesis in preterm infants for determining the anemia treatment potential of erythropoietin

Apoptosis of Peripheral CD4⁺T-Lymphocytes in End-Stage Renal Disease Patients Under Hemodialysis and rhEPO Therapies

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Neutrophil Activation and Resistance to Recombinant Human Erythropoietin Therapy in Hemodialysis Patients

Cited by 44 publications

References 33 publications

Evidence for Anti-Inflammatory Effects of Exercise in CKD

Evidence for Anti-Inflammatory Effects of Exercise in CKD

Population pharmacodynamic analysis of erythropoiesis in preterm infants for determining the anemia treatment potential of erythropoietin

Apoptosis of Peripheral CD4+T-Lymphocytes in End-Stage Renal Disease Patients Under Hemodialysis and rhEPO Therapies

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Apoptosis of Peripheral CD4⁺T-Lymphocytes in End-Stage Renal Disease Patients Under Hemodialysis and rhEPO Therapies