Evidence for the involvement of endothelial cells in the pathogenesis or
erythropoietin-induced
hypertension, and for endothelial cell damage in patients with
chronic renal failure, has emerged and appears to be of major concern. We, therefore, investigated the effect of recombinant human
erythropoietin (rHuEPO)
therapy on endothelium-derived
hormones in predialysis patients with progressive renal
anemia. At the entry to the trial, the serum
thrombomodulin concentration (Tm) and plasma
endothelin-1 concentration (ET-1) in the predialysis patients were significantly higher than those in age- and sex-matched normal subjects. Following a 16 week period of treatment with 6000IU rHuEPO given intravenously once a week, patients' hematocrit increased from 27.1 +/- 2.6% to 34.6 +/- 3.2% (n = 16, P < .001). A positive correlation was found between Tm and serum
creatinine concentration (Cr) (r = 0.61, P < .05 (n = 16), but no correlation was found between ET-1 and Cr. Tm and Tm/Cr significantly decreased from 7.9 +/- 2.8 ng/mL to 6.6 +/- 2.4 ng/mL (P < .01, n = 16), and from 2.1 +/- 0.7 (x10(-10) to 1.6 +/- 0.7 (x10(-10), P < .01, n = 16), respectively. However, there was no change in ET-1 as a result of the rHuEPO
therapy.
Creatinine clearance (Ccr), Cr, total amount of daily Tm excretion, Tm clearance/Ccr, daily urinary
protein and
albumin excretion, and blood pressure also remained unchanged throughout the trail. The present study indicates that correcting
anemia by rHuEPO
therapy reduces an abnormally elevated Tm in predialysis patients while blood pressure and renal function remain unchanged, suggesting that rHuEPO has a beneficial effect on endothelial cell dysfunction in
chronic renal failure patients. This effect may be mediated via an improved
oxygen supply to the endothelial cells due to the amelioration of
anemia by rHuEPO.