Objective. Serum levels of the soluble transferrin receptor (sTfR) vary depending on the erythropoietic activity and iron status. In vitro, sTfR shed in the incubation medium correlates well with cellular TfR, but this relationship has never been established in vivo. To determine the value of serum sTfR as a quantitative marker of the body mass of tissue TfR, we designed experiments to examine the correlation between serum sTfR and tissue TfR in rats with various degrees of erythropoietic activity or iron status. Materials and Methods. We studied changes in erythropoietic activity in normal rats as well as in animals experiencing hemolysis, phlebotomy-induced iron deficiency, transfusion-or thiamphenicol-induced erythroid aplasia, or inflammation. At the end of follow-up, ferrokinetic studies were performed and animals were sacrificed. Organs were isolated and homogenized to determine the total mass of tissue TfR from the sum of tissue solubilized TfR in the bone marrow, spleen, liver, and blood cells (direct method). An indirect method was developed to derive the corporeal mass of tissue TfR from a representative marrow sample. Results. As expected, serum sTfR and total mass of tissue TfR varied as a function of iron status and erythropoiesis. Relative erythroid expansion in the spleen was greater than in the bone marrow. With the exception of phlebotomized animals, the indirect method correlated very well with direct measurements of the total mass of tissue TfR ( r ϭ 0.97, p Ͻ 0.0001). There was a close relationship between the total mass of tissue TfR and the total mass of serum sTfR ( r ϭ 0.79, p Ͻ 0.0001). Serum sTfR represented approximately 5-6% of the total mass of tissue TfR in most experimental situations, but this ratio was twice as high during iron-restricted erythropoiesis. In addition, the ratio could be higher or lower in nonsteady-state situations, because changes in tissue TfR occurred faster than those of serum sTfR. Conclusions. Serum sTfR represents a constant proportion of the total mass of tissue TfR over a wide range of erythropoietic activity. However, iron deficiency results in a higher proportion of serum sTfR, and the pace of change in serum sTfR levels is slower than that of tissue TfR mass.

Recombinant human erythropoietin (rHuEpo) has been shown to be effective in correcting the anemia of chronic renal failure, but the dose needed may be variable. The reason for this variation is not known, but several factors could be involved, such as iron deficiency, inflammation, aluminum intoxication, hyperparathyroidism, blood losses, or marrow dysfunction. Treatment with rHuEpo was given intravenously thrice weekly after hemodialysis to 64 consecutive unselected patients with the anemia of chronic renal failure. The starting dose was 50 U/kg/dose, which was increased to 75 and 100 U/kg/dose if no response was observed after 1 and 2 months of treatment. After a minimum follow- up of 6 months, response was evaluated as early (hematocrit [Hct] > or = 30% before 3 months) or late (Hct > or = 30% after 3 months) response, or failure (target Hct not attained). We examined the value of various laboratory parameters (baseline values and early changes) as predictors of response to rHuEpo. The best prediction by pretreatment parameters only was obtained with baseline serum transferrin receptor (TfR) (< or > or = 3,500 ng/mL) and fibrinogen (< or > or = 4 g/L): 100% response rate when both parameters were low, versus only 29% when they were both high, and versus 67% when one was low and the other high. When the 2-week TfR increment was greater than 20%, the response rate was 96%. When TfR increment was less than 20%, the response rate was 100% when baseline TfR and fibrinogen were low, 12% when fibrinogen was elevated, and 62% when fibrinogen was low but baseline TfR high. The predictive value of baseline TfR and fibrinogen and of the 2-week increment of TfR was confirmed by life table analysis and stepwise discriminant analysis. Major reasons for failure or late response were identified and included subclinical inflammation, iron deficiency, functional iron deficiency, marrow disorders, hemolysis, bleeding, and low Epo dose. We conclude that response to rHuEpo can be predicted early by pretreatment fibrinogen and TfR, together with early changes of TfR levels. These prognostic factors illustrate the importance of the early erythropoietic response, subclinical inflammation, and functional iron deficiency. Early recognition of a low probability of response in a given patient could help identify and correct specific causes of treatment failure to hasten clinical improvement and avoid prolonged ineffective use of an expensive medication.

Recombinant human erythropoietin (rHuEpo) has been shown to be effective in correcting the anemia of chronic renal failure, but the dose needed may be variable. The reason for this variation is not known, but several factors could be involved, such as iron deficiency, inflammation, aluminum intoxication, hyperparathyroidism, blood losses, or marrow dysfunction. Treatment with rHuEpo was given intravenously thrice weekly after hemodialysis to 64 consecutive unselected patients with the anemia of chronic renal failure. The starting dose was 50 U/kg/dose, which was increased to 75 and 100 U/kg/dose if no response was observed after 1 and 2 months of treatment. After a minimum follow- up of 6 months, response was evaluated as early (hematocrit [Hct] > or = 30% before 3 months) or late (Hct > or = 30% after 3 months) response, or failure (target Hct not attained). We examined the value of various laboratory parameters (baseline values and early changes) as predictors of response to rHuEpo. The best prediction by pretreatment parameters only was obtained with baseline serum transferrin receptor (TfR) (< or > or = 3,500 ng/mL) and fibrinogen (< or > or = 4 g/L): 100% response rate when both parameters were low, versus only 29% when they were both high, and versus 67% when one was low and the other high. When the 2-week TfR increment was greater than 20%, the response rate was 96%. When TfR increment was less than 20%, the response rate was 100% when baseline TfR and fibrinogen were low, 12% when fibrinogen was elevated, and 62% when fibrinogen was low but baseline TfR high. The predictive value of baseline TfR and fibrinogen and of the 2-week increment of TfR was confirmed by life table analysis and stepwise discriminant analysis. Major reasons for failure or late response were identified and included subclinical inflammation, iron deficiency, functional iron deficiency, marrow disorders, hemolysis, bleeding, and low Epo dose. We conclude that response to rHuEpo can be predicted early by pretreatment fibrinogen and TfR, together with early changes of TfR levels. These prognostic factors illustrate the importance of the early erythropoietic response, subclinical inflammation, and functional iron deficiency. Early recognition of a low probability of response in a given patient could help identify and correct specific causes of treatment failure to hasten clinical improvement and avoid prolonged ineffective use of an expensive medication.

We examined the effect of treatment with rHuEpo on platelet counts in 61 hemodialysis patients and correlated them with changes in erythropoietic activity, iron status and inflammation. Platelets (109/l) increased from 220 ±80 to 245 ±102 after 14 days and stabilized at that level up to day 90 (p<0.0001). The increment was similar in complete or partial responders but was not observed in failures. Serum transferrin receptor (sTfR, a measure of total erythropoiesis) and Hct rose much more progressively, but relative platelet increments correlated with relative increases in sTfR and Hct. Relative platelet increments correlated inversely with relative changes of SeFe or transferrin saturation, but not with their absolute values, nor with baseline ferritin or its progressive decrease. Although baseline platelet count was 12% higher in patients with inflammation and correlated with serum haptoglobin, relative increases were similar in patients with or without inflammation. In conclusion, rHuEpo produced a clinically minor but consistent elevation of platelet counts. These modifications were not related primarily to modifications in iron stores, functional iron deficiency, or inflammation, but paralleled the expansion of erythropoietic activity. The results suggest that rHuEpo has a small positive effect on platelet production, but it cannot be ruled out that this could be partially mediated through functional iron deficiency.

Recombinant human erythropoietin (rHuEpo) has been shown to be effective in correcting the anaemia of chronic renal failure. It has been reported that reticulocytes as well as erythroid progenitors increase within 1-2 weeks, with no further elevation beyond this time interval. However, the erythroblast pool is quantitatively the most important compartment of erythropoiesis, and the rate, extent and duration of the expansion of erythropoietic activity in response to rHuEpo is not known. Treatment with rHuEpo was given to 64 patients i.v. thrice weekly after haemodialysis. The effect of rHuEpo was obvious from the early elevation of reticulocyte counts, but much of this increase was due to a rapid output of shift reticulocytes which levelled off after a few weeks. Serum transferrin receptor (TfR), a quantitative measure of erythropoiesis, increased progressively over 6 weeks to reach a plateau phase at about twice baseline values. The Hct increased progressively and continued to rise steadily after the TfR plateau was reached. The speed and extent of the expansion of erythropoietic activity correlated with the later haematological response to rHuEpo. When rHuEpo was discontinued, erythropoietic activity returned progressively to baseline values, to rise again gradually when treatment was resumed. Part of the Hct increase was also due to haemoconcentration. The results indicate that changes in the various erythroid compartments vary considerably in intensity and speed, and that the erythroblast compartment in particular is slow to respond to modifications in the erythropoietin stimulus.