Effects of recombinant human erythropoietin in normal humans

Abstract

This review describes some of the physiological effects of recombinant human erythropoietin (EPO) in healthy humans. At the blood level EPO increases the arterial O(2) content not only by increasing red blood cell volume, but also by an equally important decrease in plasma volume. Well before that, EPO causes a prompt decrease in plasma levels of renin and aldosterone. Renal clearance studies suggest that EPO decreases renal proximal tubular reabsorption rate leading to activation of the tubuloglomerular feedback mechanism and a fall in glomerular filtration rate. Thus, treatment with EPO may result in suppression of endogenous EPO production through a decrease in intrarenal oxygen consumption. EPO elevates the arterial blood pressure even in healthy subjects. The receptor for EPO is present in many tissues. However, the functional effects of EPO in the skeletal muscle seem limited, and although it has been speculated that non-erythropoietic effects of EPO (angiogenesis, shift in muscle fibre types, cognitive effects) may be responsible for the increase in exercise performance, this has not been confirmed. EPO-induced haemodynamic effects call for careful monitoring during the administration period. The metabolic, hormonal and renal effects of EPO do not seem to range beyond physiologically acceptable limits and are reversible. Taken together, EPO seems safe to use for experimental purposes in healthy volunteers.

Figure 1. How high levels of circulating recombinant EPO may result in suppression of endogenous EPO synthesis secondary to a decrease in intrarenal oxygen consymption, by intrinsic renal effects

(1) EPO decreases reabsorption of sodium and fluid in the proximal tubule, thereby directly reducing the major oxygen-consuming process in the kidney; (2) increase in end-proximal tubular delivery to the macula densa decreases renin release and subsequent angiotensin II- and aldosterone-dependent reabsorption in more distal nephron segments; (3) decreased proximal tubular reabsorption activates the tubuloglomerular feedback mechanism producing a fall in GFR and reduction of the filtered load; (4) the resulting increase in renal oxygen partial pressure in the environment of interstitial fibroblast-like cells down-regulates the hypoxia-inducible factor-2-dependent production of endogenous EPO.