Erythropoietin Production In Patients Research Articles

Esterification promotes the intracellular accumulation of roxadustat, an activator of hypoxia-inducible factors, to extend its effective duration

Kidney injury often causes anemia due to a lack of production of the erythroid growth factor erythropoietin (EPO) in the kidneys. Roxadustat is one of the first oral medicines inducing EPO production in patients with renal anemia by activating hypoxia-inducible factors (HIFs), which are activators of EPO gene expression. In this study, to develop prodrugs of roxadustat with improved permeability through cell membrane, we investigated the effects of 8 types of esterification on the pharmacokinetics and bioactivity of roxadustat using Hep3B hepatoma cells that HIF-dependently produce EPO. Mass spectrometry of cells incubated with the esterified roxadustat derivatives revealed that the designed compounds were deesterified after being taken up by cells and showed low cytotoxicity compared to the original compound. Esterification prolonged the effective duration of roxadustat with respect to EPO gene induction and HIF activation in cells transiently exposed to the compounds. In the kidneys and livers of mice, both of which are unique sites of EPO production, a majority of the methyl-esterified roxadustat was deesterified within 6 h after drug administration. The deesterified roxadustat derivative was continuously detectable in plasma and urine for at least 48 h after administration, while the administered compound became undetectable 24 h after administration. Additionally, we confirmed that methyl-esterified roxadustat activated erythropoiesis in mice by inducing Epo mRNA expression exclusively in renal interstitial cells, which have intrinsic EPO-producing potential. These data suggest that esterification could lead to the development of roxadustat prodrugs with improvements in cell membrane permeability, effective duration and cytotoxicity.

Anemia of chronic disease and defective erythropoietin production in patients with celiac disease

Anemia due to hematinic deficiencies is common in patients with untreated celiac disease. Although celiac disease is a chronic condition characterized by an intense inflammatory response of the intestinal mucosa, scant data are available about the prevalence of anemia of chronic disease in celiac disease. One hundred and fifty-two patients with celiac disease at presentation were studied. Anemia was investigated by determining complete blood counts, body iron status, serum levels of the soluble transferrin receptor, erythropoietin, prohepcidin and interferon-gamma. Genotyping for HFE mutations associated with hereditary hemochromatosis was performed. Fifty-three anemic patients were re-evaluated for hematologic response after 1 year on a gluten-free diet. At the time of diagnosis of celiac disease the prevalence of anemia was 34%. Fifty-three out of 65 anemic patients had either iron and/or vitamin deficiency (folate, vitamin B(12)). Hereditary hemochromatosis mutations did not affect the prevalence of anemia. In 11 cases iron status parameters were indicative of anemia of chronic disease, sometimes in association with iron deficiency (6 patients). Patients with anemia of chronic disease had low levels of erythropoietin for the degree of anemia and increased serum interferon-gamma. In most cases anemia improved following a gluten-free diet, response rates being similar in anemia of chronic disease and in anemia due to hematinic deficiencies. Our study shows that, in addition to iron and vitamin deficiencies, anemia of chronic disease has a significant role in some patients with celiac disease. Suppression of intestinal inflammatory changes as a result of a gluten-free diet improves anemia by correcting iron and vitamin malabsorption as well as mechanisms contributing to anemia of chronic disease.

Erythropoietin Production in Patients with Chronic Renal Failure

Studies were performed to reexamine the response of erythropoietin (Epo) production to acute hypoxic stimuli in patients with end-stage renal disease (ESRD). In the absence of acute bleeding or hypoxia, the serum Epo level in ESRD was similar to that of normal subjects despite severe anemia. In 11 dialysis patients with acute bleeding, the decrease in the Hb level from 8.9 to 5.8 g/dL provoked a significant increase in serum Epo up to 52.2 times the normal value. The increase in serum Epo was associated with a significant increase in corrected reticulocyte. Systemic hypoxemia (PaO2 < 65 mm Hg) in 8 dialysis patients provoked a significant elevation in the serum Epo level up to 24.6 times the normal level. There was an inverse relationship between serum Epo and arterial PaO2 (r = -0.715). The serum Epo level in these patients declined to or near the normal value after recovery from acute hypoxic stress. These data suggest that the ability of the Epo production is well preserved in ESRD, indicating that acute hypoxic stimuli provoke a significant increase in serum Epo.

Influence of the renin-angiotensin system stimulation on erythropoietin production in patients with various forms of arterial hypertension.

Recent studies suggest the existence of a relationship between the renin-angiotensin system and erythropoietin (EPO) secretion. It has been studied whether patients with various forms of arterial hypertension (essential, renal, renovascular, in the course of arteritis) differ with respect to EPO secretion and whether EPO serum levels are related to renin response induced by dietary sodium restriction to 10-20 mmol Na/24 h for 3 days and upright body position for 3 h. Patients with different forms of hypertension and normal renal excretory function and healthy subjects did not differ in hematocrit value, markers of iron metabolism, and EPO secretion except for patients with arteritis who had higher ferritin values. In these patients a positive correlation between EPO levels and hematocrit values suggests the existence of an altered regulation of EPO secretion. In essential hypertension a negative correlation found between changes in EPO and PRA levels in response to sodium restriction and upright body position may also reflect an altered regulation of both EPO and renin production.