The Acute Effect of Intravenously Administered Recombinant Human Erythropoietin on the Immune Response of Uremic Patients Maintained on Regular Hemodialysis

Abstract

The uremic patient on regular hemodialysis (RHD) is subjected to a wide range of immune modulators including the uremic state per se, multiple transfusions and exposure to bioincompatible materials and endotoxins. Erythropoietin (EPO) therapy may raise concern about its potential influence on this complex scenario. To envisage this issue, 15 adequately selected patients, stable on RHD, were randomly assigned in a 2:1 ratio into EPO and placebo groups. After initial assessment and determination of baseline values, they received, in a double-blind manner, either EPO or normal saline as an intravenous bolus immediately after termination of dialysis for 30 successive sessions. Thirty minutes later, following sessions 1, 10, 20, and 30, samples were obtained for determination of blood counts, red cell indices, peripheral lymphocyte counts (PLC), CD4/CD8 ratios, blood EPO levels, and serum concentrations of interleukins (IL) IL-2r, IL-3, and IL-6, tumor necrosis factor (TNFs and TNFalpha), and neopterin (NPT). Blood EPO levels displayed the predicted rise in the EPO group, which correlated with partial improvement of red cell parameters. The mean total leukocyte count and PLCs was significantly increased in the EPO group (p < 0.05) but not in the placebo group. CD4/CD8 ratios were not significantly changed in either group. The serum concentrations of IL-2r, IL-3, and NPT remained fairly stable while that of IL-6 was widely variable in both study groups. The mean serum concentrations of TNF and particularly TNFalpha showed a steady and statistically significant increment in the EPO group from 6 to 41 pg/ml (p < 0.05) and 93 to 128 pg/ml (p < 0.03), respectively. No significant change was noticed in the control group. It is concluded that intravenous administration of EPO under the conditions of this study may have an immune stimulating effect. This is shown by the release of TNFs, which in turn may be responsible, through different potential mechanisms, for the increase in the mean peripheral neutrophil count and the blunting of erythroid responsiveness to EPO therapy.

Neopterin measurement in clinical diagnosis

“…When added to a perfusion fluid, NP causes a decrease in erythropoietin mRNA levels. However, erythropoietin administration to patients on dialysis inhibits the release of NP only in the initial phase (23). In vivo high NP concentrations in renal tissue probably aggravate anaemia, which accompanies inflammation (41).…”

“…NP is stable for a few weeks when kept below –20 °C (8). It is measured by enzyme‐linked immunosorbent assay (ELISA), radioimmunoassay (RIA) (23) and high‐performance liquid chromatography (HPLC) (11, 24). Serum NP concentration of 10 nmol/L is accepted as the upper normal limit (6).…”

The Role of Erythropoietin and its Receptor in the Immune, Central Nervous and Cardiovascular Systems

“…After few months of rhEPO therapy decreased production of pro-inflammatory cytokines (IL-6 and TNF-α) and elevated secretion of anti-inflammatory IL-10 in whole blood cell cultures stimulated with PHA were also observed [30,31] . There were also studies showing higher concentration of TNF-α in serum of HD patients receiving rhEPO [32] but its level was determined after the dialysis procedure, during which the release of large amount of pro-inflammatory cytokines occurs [25] . Bryl et al [29,31] and Trzonkowski et al [30] demonstrated that rhEPO acts directly on production of cytokines by whole blood cells in vitro.…”