Erythropoietin (EPO) is a glycoprotein produced mainly in the kidney. After its release to
the bloodstream EPO binds to its receptor predominantly located within the bone marrow where
erythropoiesis is stimulated. Recently, we have shown that recombinant human EPO (rHuEPO)
down-regulates circulating levels of renin and aldosterone. Concomitant clearance studies
revealed a decrease in proximal tubular reabsorption of sodium and water and a fall in
glomerular filtration rate (GFR). These results for the first time demonstrate a link between
EPO and renal function: By inhibiting proximal tubular reabsorption, which in turn results in
rapid declines in GFR and renin/aldosterone levels, EPO may directly reduce the major oxygen
consuming factor in the kidney. The expected result will be an increase of the oxygen tension
in the environment of renal EPO producing cells, in this way initiating an appropriate signal
for down-regulation of endogenous EPO synthesis when circulating levels of EPO are high.
The aim of this project is to test this hypothesis by investigating the renal effects of
rHuEPO in humans. In a double-blinded manner healthy subjects will be tested with placebo, or
low-dose rHuEPO for two weeks, or high-dose rHuEPO for three days. Accurate sodium balance
studies will be conducted together with renal clearance studies for measurements of renal
plasma flow (131I-Hippuran clearance with renal venous sampling), GFR (51Cr-EDTA clearance)
and the segmentel tubular handling of sodium and water (lithium clearance).
EPO is the sole haematopoietic growth factor that is mainly produced in the kidneys and the
project will provide new information about basic physiological issues regarding the
association between renal function and the regulation of EPO synthesis.