Influence of Recombinant Human Erythropoietin Therapy on Plasma Endothelin-1 Levels during Hemodialysis

Abstract

The correction of anemia with human recombinant erythropoietin (rHuEPO) in end stage renal disease is associated with hypertension in about one third of hemodialysis patients. The pathogenesis of the rHuEPO-induced hypertension is still uncertain, though evidence of the involvement of endothelial cells has emerged. The aim of this study was to determine plasma endothelin-1 during hemodialysis and to compare the endothelin-1 levels in hemodialysis patients with and without rHuEPO substitution. Nineteen stable patients (13 male and 6 female, mean age 62 +/- 11 years) with end stage renal disease were studied. Cuprophan dialysers (GFS 12, Gambro, Lund, Sweden) were used for hemodialysis in all cases. rHuEPO (40 U/kg s.c.) was administered to 10 patients. Blood pressure (BP; RR mmHg) and blood volume changes (deltaBV; hemoglobinometry %) were serially measured. Samples were taken before and every hour during hemodialysis. Plasma endothelin-1 was measured by ELISA (R&D Systems, Minneapolis, USA) and corrected for hemoconcentration. Endothelin-1 concentration was elevated before commencement of hemodialysis (1.16 +/- 0.36 pg/ml) when compared to healthy controls (ref. 0.3-0.9) and increased to 1.47 +/- 0.51 pg/ml by the end of the session (p<0.05). In patients under rHuEPO-substitution plasma endothelin-1 was higher when compared to patients without substitution before (1.25 +/- 0.3 vs. 1.05 +/- 0.3 pg/ml) and at the end of HD (1.62 +/- 0.5 vs. 1.28 +/- 0.3 pg/ml, p<0.05). There was no difference in BP and deltaBV between the two groups during treatment. Plasma endothelin-1 was higher in hemodialysis patients and there was a continuous rise in plasma endothelin-1 during a session. Comparison of two groups of hemodialysis patients with and without s.c. rHuEPO-replacement treatment revealed a significantly higher plasma endothelin-1 concentration in patients with s.c. rHuEPO treatment. However, the elevated endothelin-1 levels were not accompanied by arterial hypertension.

The influence of erythropoietin on levels of endothelin‐1 and nitric oxide in patients on hemodialysis

“…The level of ET-1 is signifi cantly higher in the patients treated with hemodialysis when compared with the control group. Unlike previous studies, 8,15 we noticed a signifi cant decrease of the level of ET-1 and NO after dialysis compared to the values before dialysis, which we attribute to the characteristics of our group. A similar result was discovered in the patients treated with hemodialysis in the subgroup of the patients with stable values of pressure during the research of Raj et al 9 Unlike previous studies, 10,15 we did not fi nd signifi cant correlation between the weekly dosage of erythropoietin and the serum levels of ET-1 and NO, neither before, nor after treatment with dialysis.…”

“…However, the increased levels of ET-1 were not followed by an increase of blood pressure. 15 Takahasi et al showed that the level of ET-1 in plasma in hemodialysis patients grew only in patients whose intradialytic pressure increased by 10 mmHg after 8 weeks of using rhEPO. 11 Studies with patients with intradialytic hypertension show a signifi cant increase of ET-1 during dialysis and a signifi cant decrease of the ET-1/NO ratio at the end of dialysis.…”

“…The balance irregularities of local endothelin factors, such as endothelin-1 (ET-1) and nitric oxide (NO), are one of the suggested possible mechanisms included in hypertension caused by erythropoietin. [7][8][9][10][11][12][13][14][15] Endothelins are regulatory peptides, distributed in many organic systems with a strong physiological function.In 1988, Yanagisava isolated, sequenced, and cloned 21 amino acids from a fraction of unhomogenized endothelin cells and named them endothelin. 16 Yanagisava also isolated 2 isoforms of endothelin, different from the original endothelin in the second and sixth amino acid, and named them endothelin-2 and endothelin-3.…”

“…The balance irregularities of local endothelin factors, such as endothelin-1 (ET-1) and nitric oxide (NO), are one of the suggested possible mechanisms included in hypertension caused by erythropoietin. [7][8][9][10][11][12][13][14][15] Endothelins are regulatory peptides, distributed in many organic systems with a strong physiological function.…”

Arterial Hypertension Induced by Erythropoietin and Erythropoiesis-Stimulating Agents (ESA)

“…Several studies have found that Epo-induced hypertension in hemodialyzed patients was associated with significantly increased circulating ET-1 concentrations (75)(76)(77) and that the accentuated ET-1 response to Epo was particularly great in the patients who exhibited the highest pressure response to Epo (74). In contrast to angiotensin II and norepinephrine, however, no ET-1 hypersensitivity was found, as evidenced by the similar changes in forearm resistance in response to ET-1 infusions with and without Epo (70).…”