Erythropoietin down‐regulates proximal renal tubular reabsorption and causes a fall in glomerular filtration rate in humans

Non-technical summary  Recombinant human erythropoietin (rHuEPO) decreases circulating levels of renin and aldosterone, two hormones regulating water and salt homeostasis, but the effect of rHuEPO on renal function is unknown. This study demonstrates that rHuEPO reduces the reabsorption of water and sodium in the proximal renal tubules and, probably by activation of the tubuloglomerular feedback mechanism, also causes a fall in glomerular filtration rate. Thus, the decrease in plasma concentrations of renin and aldosterone may be secondary to increased end-proximal tubular delivery of water and sodium. In conclusion, the fall in proximal reabsorption together with a reduced filtered load and a decrease in angiotensin II and aldosterone-dependent tubular reabsorption are expected to increase the oxygen tension in the renal tissue. This may serve to down-regulate the endogenous renal synthesis of EPO in the presence of high levels of circulating rHuEPO. Abstract  Recombinant human erythropoietin (rHuEPO) elevates haemoglobin concentration both by increasing red blood cell volume and by a decrease in plasma volume. This study delineates the association of rHuEPO-induced changes in blood volumes with changes in the renin–aldosterone system and renal function. Sixteen healthy males were given rHuEPO for 28 days in doses raising the haematocrit to 48.3 ± 4.1%. Renal clearance studies with urine collections (N= 8) were done at baseline and at days 4, 11, 29 and 42. Glomerular filtration rate (GFR) was measured by 51Cr-EDTA. Renal clearance of lithium (CLi) was used as an index of proximal tubular outflow and to assess segmental renal tubular handling of sodium and water. rHuEPO-induced increases in haematocrit occurred from day 10 onwards and was caused by both an increase in red cell volume and a fall in plasma volume. Well before that (from day 2 and throughout the treatment time), rHuEPO decreased plasma levels of renin and aldosterone (N= 8) by 21–33% (P < 0.05) and 15–36% (P < 0.05), respectively. After cessation of rHuEPO, values returned to baseline. On days 11 and 29, CLi increased (P < 0.02) indicating a significant 10–16% decrease in absolute proximal reabsorption of sodium and water (APR = GFR −CLi, P < 0.05). GFR decreased slightly, albeit significantly, on day 4 (P < 0.05). In conclusion, rHuEPO promptly, and before any changes in blood volumes and haematocrit can be detected, causes a down-regulation of the renin–aldosterone system. The results are compatible with a rHuEPO-induced reduction in proximal reabsorption rate leading to activation of the tubuloglomerular feedback mechanism and a fall in GFR. Therefore, treatment with rHuEPO may result in suppression of endogenous EPO synthesis secondary to a decrease in intrarenal oxygen consumption.