Quantification of the Erythropoietic Response to Anemia and Determination of the Hb × log(Epo) Component as an Independent Parameter, Indicating the Response to Hypoxic Stress

Abstract

Serum erythropoietin (Epo) levels are influenced by the integrity of renal function, the severity and etiology of anemia, the percentage of hemoglobin F and other factors. We aimed to create a parametric expression for the response to anemic/hypoxic stress and we evaluated serum Epo levels in 1096 subjects with normal renal function, of whom 837 were anemic (Hb < 12 g/dl), 204 were non anemic (Hb 12 - 16.5 g/dl), and 55 were erythremic (Hb > 16.5 g/dl). Hb ranged between 3.6 and 23.8 g/dl and the corresponding Epo between <3.4 and 2670 mIU/ml. Between log-Epo and Hb the correlation co-efficient r was ?0.706. The function linking Hb and log-Epo was determined as log(Epo) = 3.05 - 0.131 × Hb. Investigating various mathematic models, which could parametrically express the “response to anemia/hypoxia”, we found that the Hb × log(Epo) product was a stable parameter and fitted a normal distribution. Arbitrarily defining as normal range about one SD between the mean (12 - 21) we found that only 224 patients (20.8%) exhibited a Response to Anemia Index (RAI) beyond these limits. Below the lower limit there were 106 patients, diagnosed with polycythemia vera (12/38, 31.6%) anemia of chronic disease (10/34, 29.4%), megaloblastic anemia (17/56, 30.4%) and β-thalassemia trait (11/41, 26.8%). Forty-eight patients (45.3%) were diabetic. Above the defined upper normal RAI limit there were 118 patients, mainly diagnosed with secondary erythrocytosis (24/34, 70.6%), aplastic anemia (8/20, 40%), hemolytic anemia (3/14, 21.4%) and myelodysplastic syndromes (46/326, 14.1%). RAI was a rather constant parameter for each individual, with minimal variation in different evaluations, when Epo was estimated in the absence of inflammatory conditions. We have validated the superiority of RAI for the prediction of response to Epo in a cohort of 669 patients, who received Epo treatment. It is concluded that RAI is a reliable parameter describing the response to hypoxic/anemic stress.