Erythropoietin Inhibitor in Kidney Extracts and Plasma from Anemic Uremic Human Subjects

1. An erythropoietin inhibitor has been demonstrated in human kidney homogenates from two patients with chronic renal insufficiency and two normal human subjects. The level of the inhibitor was significantly higher in the nephritic kidney homogenates than that of the normal kidneys. The ESF inhibitor was found in the soluble cytoplasmic fraction of the kidney, using an osmotic sucrose gradient and differential centrifugation technic. The inhibitor was still present after in vitro dialysis of the kidney soluble fractions and was partially inactivated by boiling. 2. The nuclear and mitochondrial fractions from the normal and nephritic kidneys markedly accentuated the erythropoietic activity of human urinary ESF when injected simultaneously at separate sites in polycythemic mice. The accentuating effects on ESF of the above fractions was significantly less in the nephritic than in the normal kidneys. 3. Flat bed discontinuous acrylamide gel electrophoresis studies on the kidney homogenates revealed a marked increase in the concentration of protein and a decrease in esterase activity in the albumin fractions in the nephritic kidney when compared with those of the normal kidneys. An additional band between the albumin and alpha-1-globulin regions was detected in the nephritic kidney fractions which was not present in the normal kidney fractions. The significance of these observations as they may relate to the inhibitor is discussed. 4. Plasma from five out of six anemic uremic subjects produced a significant inhibition of ESF; while normal human plasma was found to accentuate the erythropoietic effects of ESF. 5. A marked enhancement of the erythropoietic effects of human urinary ESF by human liver homogenate was also seen. 6. It is postulated from these studies that the anemia of chronic renal insufficiency is due, at least in part, to erythroid failure resulting from a lack of available erythropoietin. This deficiency in erythropoietin activity is probably due to an increase in an ESF inhibitor and/or a decrease in a renal erythropoietic factor (REF).