The Role of the Kidney in the Erythropoietic Response to Hypoxia in Parabiotic Rats

By WENDELL F. ROSSE AND THo IAs A. WALDMANN T HE EXISTENCE of a specific hunioral substance stimulating erythropoiesis ( erythropoietin, erythropoiesis stimulating factor, ESF ) was first suspected by Carnot and Defiandre in 1906’ and has since been amply confirmed.2 The site of production of this substance is the subject of considerable controversy. The occurrence of erythrocytosis with renal tumors’ and cysts4 and with hydronephrosis5 and the presence of anemia in chronic renal disease6 suggest that the kidney may be an important site. Some investigators (Jacobson et al.,7 Naets,8’#{176} Reissmann et al.,1#{176} ) have not been able to demonstrate ESF in the serum of nephrectomized anemic. anoxic or cobalt-treated animals, whereas others ( Mirand et Piliero et Gallagher et al.’ have found increased serum ESF in response to some stimuli. The differences in the results may reflect the relative insensitivity of the assay systems used, which depend upon the injection of serum from the stimulated animals into recipient animals. Measurement of erythropoiesis directly in the animal stimulated by hypoxia, anemia or cobalt is a more sensitive system for measuring the presence of ESF than the indirect measurement which these workers used. Unfortunately, nephrectomized animals develop significant ufemia in spite of peritoneal lavage before adequate stimulus can be given and response measured. Lack of erythropoietic response to anemia in such nephrectomized animals has been interpreted as being due to either the absence of the site of production8’#{176} or to the metabolic effects of uremia.l4,la Parabiosis provides a preparation in which nephrectomy can be performed in one partner with survival of that partner and without uremic suppression of erythropoiesis of the other partner. Reissmann has shown that ESF passes from one animal to the other in such a preparation.1#{176} Therefore, we chose to use parabiotic rats in an effort to estimate the role of the kidney and of extrarenal sites in the erythropoietic response to hypoxia.