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

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 studieswith 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.

Figure 1. Relative changes in blood volumes

N = 16. Values are means (s.d.). *P < 0.05 compared with baseline.

Figure 2. Plasma concentrations or renin and aldosterone

Plasma concentrations of renin and aldosterone before (0) and after 2, 4, 6, 10, 14, and 28 days of treatment with rHuEpo and after 1 week (Day 35), 2 weeks (Day 42), and 3 weeks (Day 49) after the last injection. N = 8. Values are means (s.d.). *P < 0.05 compared with baseline.

Figure 3. Glomerular filtration rate, lithium clearance and absolute proximal reabsorbtion rate

Glomerular filtration rate (A), lithium clearance (B), and absolute proximal reabsorbtion rate (C) before injections with rHuEpo (baseline) and following 4 weeks of rHuEpo treatment (days 11 and 29) and again after two weeks with no injections (day 42). N = 8. Values are means (s.d.). *P < 0.05 compared with baseline values.