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

Abstract

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 51 Cr-EDTA. Renal clearance of lithium (C Li ) 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, C Li increased (P < 0.02) indicating a significant 10-16% decrease in absolute proximal reabsorption of sodium and water (APR = GFR − C Li , 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.

Whole body metabolic effects of prolonged endurance training in combination with erythropoietin treatment in humans: a randomized placebo controlled trial

“…Plasma clearance of infused insulin is mainly renal, as opposed to endogenous insulin, which to a major extent is subjected to a first-pass metabolism in the liver, and occurs by both glomerular filtration and proximal tubular reabsorption and degradation (11). Prolonged treatment with rHuEpo decreases proximal tubular reabsorption and glomerular filtration rate (42). This could explain the slower clearance of insulin during the clamp in the ESA-treated subjects.…”

Divergent physiological responses in laboratory rats and mice raised at high altitude

“…The enhanced Hct value in rats might be due to a more sensitive hypoxia-sensing system in the kidneys, which could include stabilization of the hypoxic inducible factor (HIF), expression of HIF regulatory proteins and/or synthesis of erythropoietin (Epo) (Franke et al, 2013). In addition, it is worth mentioning that the synthesis of Epo in the kidney is regulated by the glomerular filtration rate (Olsen et al, 2011) because the consumption of O 2 in the kidneys (a major determinant of local P O2 ) is tightly dependent on sodium reabsorption and glomerular filtration rate (Donnelly, 2001). Accordingly, a lower glomerular filtration rate and/or sodium reabsorption in mice compared with rats could contribute to lower Epo production and reduced Hct.…”

The effect of erythropoietin on glomerular filtration rate in patients with chronic kidney disease and mild anemia in terms of diabetic nephropathy

“…Applying recombinant human erythropoietin in the treatment of these patients reduce the complications of anemia in such patients (8). In the present study, it was indicated that CKD patients' GFR was 76.95±5.97 before the prescription of erythropoietin.…”