Early prediction of response to recombinant human erythropoietin in patients with the anemia of renal failure by serum transferrin receptor and fibrinogen

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 in the anemia associated with multiple myeloma or non-Hodgkin's lymphoma: dose finding and identification of predictors of response

Previous phase I-II clinical trials have shown that recombinant human erythropoietin (rHuEpo) can ameliorate anemia in a portion of patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). Therefore, we performed a randomized controlled multicenter study to define the optimal initial dosage and to identify predictors of response to rHuEpo. A total of 146 patients who had hemoglobin (Hb) levels < or = 11 g/dL and who had no need for transfusion at the time of enrollment entered this trial. Patients were randomized to receive 1,000 U (n = 31), 2,000 U (n = 29), 5,000 U (n = 31), or 10,000 U (n = 26) of rHuEpo daily subcutaneously for 8 weeks or to receive no therapy (n = 29). Of the patients, 84 suffered from MM and 62 from low- to intermediate-grade NHL, including chronic lymphocytic leukemia; 116 of 146 (79%) received chemotherapy during the study. The mean baseline Hb level was 9.4 +/- 1.0 g/dL. The median serum Epo level was 32 mU/mL, and endogenous Epo production was found to be defective in 77% of the patients, as judged by a value for the ratio of observed-to-predicted serum Epo levels (O/P ratio) of < or = 0.9. An intention-to-treat analysis was performed to evaluate treatment efficacy. The median average increase in Hb levels per week was 0.04 g/dL in the control group and -0.04 (P = .57), 0.22 (P = .05), 0.43 (P = .01), and 0.58 (P = .0001) g/dL in the 1,000 U, 2,000 U, 5,000 U, and 10,000 U groups, respectively (P values versus control). The probability of response (delta Hb > or = 2 g/dL) increased steadily and, after 8 weeks, reached 31% (2,000 U), 61% (5,000 U), and 62% (10,000 U), respectively. Regression analysis using Cox's proportional hazard model and classification and regression tree analysis showed that serum Epo levels and the O/P ratio were the most important factors predicting response in patients receiving 5,000 or 10,000 U. Approximately three quarters of patients presenting with Epo levels inappropriately low for the degree of anemia responded to rHuEpo, whereas only one quarter of those with adequate Epo levels did so. Classification and regression tree analysis also showed that doses of 2,000 U daily were effective in patients with an average platelet count greater than 150 x 10(9)/L. About 50% of these patients are expected to respond to rHuEpo. Thus, rHuEpo was safe and effective in ameliorating the anemia of MM and NHL patients who showed defective endogenous Epo production. From a practical point of view, we conclude that the decision to use rHuEpo in an individual anemic patient with MM or NHL should be based on serum Epo levels, whereas the choice of the initial dosage should be based on residual marrow function.     

High-dose alfacalcidol improves anaemia in patients on haemodialysis

BACKGROUND: Alfacalcidol is efficient for treating secondary hyperparathyroidism in patients on maintenance haemodialysis (HD). Little is known about the direct impact of high-dose alfacalcidol on anaemia in end-stage renal failure. We therefore carried out a prospective study over 18 months to examine the direct effect of high-dose alfacalcidol on erythropoiesis in erythropoietin (rHuEpo)-dependent anaemic patients on HD for more than 6 months with moderate hyperparathyroidism. STUDY DESIGN: Twelve patients received oral alfacalcidol at a dosage of 6-7 micrograms per week and calcium carbonate during the first 12 months, calcium carbonate without alfacalcidol during the next 3 months, and again alfacalcidol and calcium carbonate during the last 3 months. Criteria for selection were haemoglobin < 10 g/dl, iPTH > 250 pg/ml, transferrin saturation (TS) > 25%, S-ferritin > 300 micrograms/l, and S-aluminium < 40 micrograms/l. RESULTS: Haemoglobin (Hb) and reticulocyte counts increased during the first phase, decreased and returned to a baseline prior to starting vitamin D treatment in the second phase, and again increased when alfacalcidol was reintroduced, whereas iPTH decreased during the first 3 months of the first phase and then remained stable, as did S-calcium, which increased during the first 3 months and then remained constant. S-phosphate increased during the first and third phases, and decreased during the second phase. Two patients during the first phase and one patient during the third phase presented hypercalcaemia; requiring a temporary discontinuation of alfacalcidol. CONCLUSION: High-dose alfacalcidol is efficient in anaemic patients with moderate hyperparathyroidism on maintenance HD and has a direct effect on erythropoietic cells regardless of serum calcium and iPTH levels.     

The effect of subcutaneous recombinant human erythropoietin (r-HuEPO) on anemia in cancer patients receiving platinum-based chemotherapy

Advanced cancer is commonly associated with significant anemia which worsens with the administration of cytotoxic drugs. Erythropoietin (EPO) levels in these patients are usually inappropriately low for the degree of anemia. We evaluated the effect of subcutaneous administration of recombinant human erythropoietin (r-HuEPO) on hematologic parameters and transfusion requirements in anemic cancer patients who were receiving platinum-based chemotherapy. Baseline studies included complete hemogram, reticulocyte count, serum iron, TIBC, ferritin and determination of performance status and quality of life (QOL). Twenty-three patients, 13 females, 10 males with mean age 52 years received 150 units/kg of r-HuEPO three times weekly for a minimum of 10 weeks. They also received supplemental iron. Ovarian cancer was the commonest underlying malignancy. Most of the patients received platinum-based combination chemotherapy. Mean duration of r-HuEPO therapy was 12.6 weeks. Average baseline reticulocyte count was 1.8% which increased to 7.0% after one week therapy. Eight patients had normalization of hemoglobin values. Another eight patients improved their hemoglobin by at least 2 g/dl, however, hemoglobin values remained below the normal range. Two patients had only slight increase in hemoglobin but never required blood transfusion. Three patients who were transfusion dependent had decrease in the transfusion requirements. Two patients had no significant benefit. In most patients response was evident within 2 weeks. All responders had improvement in QOL. No significant toxicity was observed. We conclude that r-HuEPO, given subcutaneously, is highly effective in amelioration of anemia and prevention of or reduction in transfusion requirements in cancer patients receiving platinum-based chemotherapy.     

Transfusion and recombinant human erythropoietin requirements differ between dialysis modalities

BACKGROUND: Before the routine use of recombinant human erythropoietin (rHuEpo), patients dialysed by peritoneal dialysis (PD) received fewer blood transfusions than patients on haemodialysis (HD). We compared transfusion practices in these groups now that the use of rHuEpo has become standard, while controlling for variables known to influence anaemia of end-stage renal disease (ESRD). Maintenance rHuEpo doses were also compared. METHODS: Data were examined for 157 HD and 126 PD patients during a 2-year period. Potential confounders included age, gender, albumin, iron deficiency, parathyroid hormone (PTH), underlying renal disease, comorbid illness, renal transplant, dialysis adequacy and duration. An intent-to-treat analysis was used, with sensitivity analyses to account for change in treatment and transplant. RESULTS: Mean haemoglobin (Hb) was not different (10.47 g/dl for HD, 10.71 g/dl for PD; P = 0.45). Mean monthly transfusion rate was higher for HD (0.47 units per month vs 0.19; P < 0.01). More HD patients received at least one transfusion (52.9 vs 40.9%; P < 0.01). The maintenance rHuEpo dose was higher for HD (7370 U/week vs 5790 U/week; P = 0.01). The only factors associated with risk of being transfused were dialysis duration and mode of dialysis (less risk for PD, odds-ratio 0.57; 95% confidence interval 0.35-0.92). CONCLUSIONS: Despite the routine use of rHuEpo, HD patients received more blood and rHuEpo than PD patients to achieve the same Hb. No patient factors were identified to account for this difference. The use of fewer transfusions and less rHuEpo in PD represents an advantage over HD in terms of both cost and safety.     

Origin and function of epoxyeicosatrienoic acids in vascular endothelial cells: more than just endothelium-derived hyperpolarizing factor?

We studied the influence of erythropoietin (EPO) treatment on hemoglobin A1c (HbA1c) levels under conditions which eliminate the effect of changes in the blood glucose concentration. HbA1c levels, blood glucose, hematocrit (Hct) and reticulocyte counts were serially measured every two weeks after starting or stopping EPO administration in 15 non-diabetic hemodialysis patients. EPO treatment significantly influenced HbA1c levels, and the more erythropoiesis fluctuated by changing the dose of EPO, the more HbA1c levels changed, though there were no significant changes in blood glucose levels during the study period. The changes in HbA1c during the 2-week period correlated inversely with both the changes in Hct during the same 2 weeks and the reticulocyte counts at that time. We concluded that the change in Hct should be kept in mind when the HbA1c level is evaluated in EPO-treated patients and a formula should be proposed to correct HbA1c levels based on the change in Hct or the reticulocyte count.     

Perisurgical erythropoietin application in anemic patients with colorectal cancer: A double-blind randomized study

BACKGROUND: Blood transfusions are associated with higher postoperative morbidity and tumor recurrence rates in colorectal cancer surgery, To reduce the need for transfusions in patients with tumor-induced anemia who are not suitable for autologous blood donation, it was tested whether perisurgical erythropoietin application would be able to stimulate hematopoiesis adequately. METHODS: In a double-blind randomized study 150 IU/kg body weight erythropoietin was given subcutaneously every 2 days beginning 10 days before operation and continuing until postoperative day 2. Twenty patients were randomized into the erythropoietin group with three observed dropouts and 10 patients into the placebo group. RESULTS: In the erythropoietin group two episodes of hypertension and one deep venous thrombosis were observed. Preoperative hemoglobin response in the erythropoietin group (p = 0.069) was paralleled by a highly significant reticulocyte increase (p = 0.0004). However, frequency of blood transfusion was not different between both study groups (erythropoietin, 1.82 +/- 0.80 units/ patient; placebo, 1.80 +/- 0.97 units/patient). If iron availability was analyzed, a strong correlation between ferritin blood levels and transferrin iron saturation with hemoglobin response was observed in regression analysis (p < 0.001). CONCLUSIONS: These results indicate that hematopoiesis in anemic patients with colorectal cancer can be stimulated by erythropoietin; however, clinical efficacy is to be expected only in selected patients with high iron availability, which calls for further studies combining erythropoietin and parenteral iron application.     

Increased autologous blood donation in rectal cancer by recombinant human erythropoietin (rhEPO)

A randomised, placebo-controlled trial was conducted to study whether the subcutaneous administration of recombinant human erythropoietin (rhEPO) increases the donated red cell blood volume in patients with rectal cancer. Patients with resectable rectal cancer and a haemoglobin (Hb) level > or = 12.5/ > 12 g/dl (males/females) were scheduled to receive pre-operatively either erythropoietin (200 U/kg body weight daily) (n = 28) or placebo (n = 26) subcutaneously for 11 days. During this period autologous blood was collected. No serious adverse events were attributed to erythropoietin. 20 of 28 patients treated with rhEPO were able to donate > or = 3 units (71%) compared with 11 of 26 control patients (42%). The mean cumulative volume of red cells donated was 29% higher in the patients who received rhEPO (571 versus 444 ml, P = 0.02). The change in the mean reticulocyte value from baseline to the last pre-operative value was significantly higher in the rhEPO group (10.4 to 61.6/1000 versus 11.0 to 20.1/1000, P = 0.0001). The fall in the mean haematocrit from baseline to the last pre-operative value was significantly lower in the rhEPO group (41.4 to 37.6% versus 41.8 to 34.8%, P = 0.0004). rhEPO increases the ability of cancer patients to donate autologous blood during a short pre-operative period and enhances the restoration of haematological values after the donation period.     

Percentage hypochromic red cells and the response to intravenous iron therapy in anaemic haemodialysis patients

INTRODUCTION: Iron deficiency is commonly encountered in haemodialysis (HD) patients and may be overcome by i.v. iron therapy. We have examined the percentage hypochromic red cells (%HRC) for predicting response to i.v. iron in subjects with a low serum ferritin. METHODS: Prospective study of i.v. iron saccharate (trivalent iron 200 mg/week for 8 weeks) in anaemic (Hb < 10 g/dl) HD patients with serum ferritin < 100 microg/l despite oral iron therapy. Response to i.v. iron was assessed by comparing Hb at 0 and 8 weeks according to %HRC at baseline (0-3%, 4-9%, > or = 10%). Results are mean+/-1 SD. RESULTS: For all subjects (n=82), Hb and ferritin increased between 0 and 8 weeks (8.9+/-1.0 to 10.1+/-1.4, P<0.0001; 55+/-24 to 288+/-126, P<0.0001). Patients were stratified into three groups according to %HRC at baseline (0-3%, 4-9%, > or = 10%). Hb increased significantly in all three groups. The mean increase in Hb was greater (0-3%, 0.6+/-1.2; 4-9%, 1.2+/-1.0; > or = 10%, 1.6+/-1.4; P=0.02) and the proportion of patients showing a > or = 1 g/dl increase in Hb was greater (0-3%, 27%; 4-9%, 57%; > or = 10%, 67%; P=0.02) in those with the largest %HRC pre-treatment. CONCLUSION: Intravenous iron therapy is effective in improving Hb in anaemic HD patients with a low ferritin. However, the magnitude of this response and the proportion of patients responding is related to the percentage hypochromic red cells prior to treatment.     

Hydrogen peroxide induces protection against lethal effects of cumene hydroperoxide in Escherichia coli cells: an Ahp dependent and OxyR independent system?

Despite a large body of evidence showing the beneficial effects of successful treatment of anemia with recombinant human erythropoietin (EPO) in patients with end-stage renal disease, controversy remains as to whether EPO treatment of anemia can improve the nutritional status in patients on maintenance hemodialysis. This prompted us to conduct a prospective study in 41 hemodialysis patients with basal hemoglobin less than 9 g/dl. The dose of EPO was increased for 12 weeks to achieve the target hemoglobin concentration of 10 g/dl and then titrated in the following 12 weeks to maintain the target value. Nutritional status was assessed at baseline and after 6 months of follow-up, using the global protein-calorie malnutrition (PCM) index proposed by Bilbrey and Cohen. A low global PCM score indicates better nutrition. The results showed that hemoglobin values significantly increased from 8.7 +/- 0.8 g/dl at baseline to 10.7 +/- 0.5 g/dl in the 6th month (p < 0.001). No significant changes were observed in the normalized protein catabolic rate and Kt/V during the study period. Global PCM scores improved from 30.0 +/- 7.5 to 23.6 +/- 3.1 (p < 0.001) and paralleled the correction of anemia by EPO treatment. The data were consistent with a major improvement in the nutritional markers of relative body weight, triceps skinfold, midarm circumference, midarm muscle circumference, serum albumin, serum transferrin and total lymphocyte count in the 6th month as compared to baseline. The percentages of mild and moderate-severe PCM at baseline were 32 and 58%, respectively. These percentages were significantly reduced during the 6th month to 20 and 30%, respectively (p = 0.0004). In summary, correction of renal anemia with EPO improves the nutritional status in hemodialysis patients. A postulated mechanism is that EPO may exhibit anabolic effects, with a better utilization of ingested protein.     

Treatment with recombinant human erythropoietin (rHuEpo) in a patient with paroxysmal nocturnal haemoglobinuria: evaluation of membrane proteins CD55 and CD59 with cytofluorometric assay

We describe a 28-year-old man with paroxysmal nocturnal haemoglobinuria (PNH) and a high transfusion requirement. Prior to and during therapy with recombinant human erythropoietin (rHuEpo), we evaluated the levels of 'decay-accelerating-factor', CD55, and 'membrane-inhibitor-of-reactive-lysis', CD59, as markers of the disease, whilst CD58, a marker present on leucocytes, was utilized to monitor normal haemopoietic activity. The patient became transfusion independent 1 month after beginning rHuEpo and remains well. The analysis of CD55, CD59 and CD58 suggests that the efficacy of rHuEpo was due to a selective rHuEpo action on normal erythroid clones.     

Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin in athletes. Blood sampling and doping control

1. The pharmacokinetics of recombinant human erythropoietin (rHuEpo) were initially determined in two healthy volunteers after a single subcutaneous dose (50 u kg-1). Twenty subjects then received repeated subcutaneous administrations of high dose (200 u kg-1) rHuEpo and 10 subjects received placebo. An immunoradiometric assay was used to measure the concentrations of erythropoietin (Epo) in serum and urine. 2. Serum Epo concentration-time profiles were best described by a one-compartment open model with zero-order input. The mean elimination half-life (+/- s.d.) was 42.0 +/- 34.2 h. Clearance, uncorrected for bioavailability, was 0.05 +/- 0.011 h-1 kg-1. Erythropoietin concentrations returned to normal values in serum and urine, 7 and 4 days after the last administration, respectively. 3. The recombinant hormone was well tolerated. Significant changes in reticulocytes and red blood cells, haemoglobin concentrations and haematocrit were observed after administration of rHuEpo. In the control group, these parameters remained unchanged. 4. The change in reticulocytes was used as an index of the therapeutic effect of rHuEpo. The concentration-effect relationship was best described by an exponential model. 5. These data show the limitations of the measurement of Epo concentrations in blood and urine samples, collected in athletes during competition, for antidoping control. Epo doping can be detected only during or within 4 to 7 days of ending a course of rHuEpo.     

Altitude training at 2690m does not increase total haemoglobin mass or sea level VO2max in world champion track cyclists

Haemoglobin mass (Hb mass), maximum oxygen consumption (VO2max), simulated 4000 m individual pursuit cycling performance (IP4000), and haematological markers of red blood cell (RBC) turnover were measured in 8 male cyclists before and after (A) 31 d of altitude training at 2690 m. The dependent variables were measured serially after altitude on d A3-4, A8-9 and A20-21. There was no significant change in Hb mass over the course of the study and VO2max at d A9 was significantly lower than the baseline value (79.3 +/- 0.7 versus 81.4 +/- 0.6 ml x kg(-1) x min(-1), respectively). No increase in Hb mass or VO2max was probably due to initial values being close to the natural physiological limit with little scope for further change. When the IP4000 was analysed as a function of the best score on any of the three test days after altitude training there was a 4% improvement that was not reflected in a corresponding change in VO2max or Hb mass. RBC creatine concentration was significantly reduced after altitude training, suggesting a decrease in the average age of the RBC population. However, measurement of reticulocyte number and serum concentrations of erythropoietin, haptoglobin and bilirubin before and after altitude provided no evidence of increased RBC turnover. The data suggest that for these elite cyclists any benefit of altitude training was not from changes in VO2max or Hb mass, although this does not exclude the possibility of improved anaerobic capacity.     

The impact of early normalization of haematocrit by erythropoietin on renal damage in the remnant kidney model

BACKGROUND: Correction of anaemia in moderate to advanced renal failure is still a matter of debate because of postulated detrimental effects of erythropoietin on the progression of renal damage. METHODS: The renal effects of early normalization of haematocrit (Htc) by erythropoietin (rHuEpo) were investigated from the time of 5/6 nephrectomy up to 8 weeks post-intervention in three groups of remnant kidney model rats: untreated controls (CON), rats receiving 100 UI/kg body-wt of rHuEpo i.p. twice a week (EPO), and rats receiving rHuEpo in which periodic phlebotomies maintained Htc similar to the value of the control group (PHL). The latter group was included to evaluate the direct effects of rHuEpo on renal damage, i.e. independent from Htc correction. RESULTS: Two weeks after renal ablation (basal), Htc decreased in CON and PHL rats (from 49.3+/-1.4% to 43.2+/- 1.1, P < 0.05 and from 49.6+/-1.1 to 43.3+/-1.5%, P<0.05 respectively), while it remained consistently normal in EPO rats (48.9+/-1.2% to 48.9+/-1.50/%, P<0.05 vs other groups). Thereafter Htc did not change throughout the remaining period in all groups. At the end of the study, with respect to basal, resting blood pressure increased significantly by the same extent in CON (+ 13+/-2%) and EPO rats (+ 15+/-5%), while it remained constant in PHL rats. Notably, creatinine clearance significantly decreased in CON (-53+/-8% 8 vs basal) and EPO (-38+/-8% vs basal), while it did not change in PHL rats. Likewise the degree of proteinuria as well as renal morphologic alterations and glomerular hypertrophy/sclerosis was similar in CON and EPO rats, and was significantly more severe than in the phlebotomized group. The only difference detected between CON and EPO group was the greater mesangial hypercellularity in rHuEpo-treated rats. CONCLUSION: In uraemic rats, chronic treatment with rHuEpo aimed at normalization of Htc beginning the early stage of renal failure does not inevitably account for a rise in systemic blood pressure. In addition, neither erythropoietin per se nor the correction of haematocrit accelerates the progression of renal damage when blood pressure remains constant.     

Erythropoietin modified the cardiac action of ouabain in chronically anaemic-uraemic rats

The results of the studies reported here demonstrate the cardiac non-haematopoietic effect of erythropoietin, providing a new physiological function of the hormone. We demonstrate that myocardium from rat with chronic renal failure (CRF) showed an abnormal response to ouabain associated with an inhibition of cardiac Na+/K+/ATPase activity and with a decrease in the high affinity 3H-ouabain binding sites. The extent to which both actions were improved with the recombinant human erythropoietin (rHuEpo) treatment suggests that the lack of the hormone is responsible for this phenomenon. The fact is that neither contractile nor enzymatic action of rHuEpo was accompanied with the improvement of the functional renal and haematologic parameters, indicating a primary effect on myocardial contractile function of rHuEpo, independent of the anaemic and uraemic state of the animal. The reason why erythropoietin is able to modulate directly the cardiac Na+/K+ pump makes it possible to conclude that the lack of erythropoietin in CRF may be at least in part responsible for the inhibition of cardiac enzymes, altering the contractile behaviour of the heart.     

Nonreentrant supraventricular tachycardia due to double ventricular response via dual atrioventricular nodal pathways

In twenty eight patients with iron deficiency the efficacy of iron-acetil-transferrin treatment (2-3 mg/kg/die) has been evaluated from the changes of the following variables: RBC and reticulocyte count, Hb concentration, MCV, MCH, serum ferritin, serum iron, TIBC, and ZnPP. These variables were assessed before and after three months of treatment in all patients, and after three months from the end of the treatment in thirteen patients. At the end of the treatment there was a significant increase of RBC count, Hb concentration, MCV, MCH, serum ferritin, serum iron, and TIBC, a significant decrease of ZnPP, while reticulocyte count remained essentially unchanged. After three months from the end of the treatment only serum ferritin and ZnPP underwent an additional significant increase and decrease, respectively. In twenty-six patients serum ferritin values returned to normal. The changes of RBC and reticulocyte count, Hb concentration, MCV, serum iron, and TIBC were larger the lower the initial values, suggesting that the efficacy of the treatment is greater the more serious the iron deficiency.     

Follow-up of TIPS: evaluation of signs of dysfunction with Doppler ultrasonography

The anemia of malignancy is common and is related to several etiologic factors, a major one being relative erythropoietin (Epo) deficiency. Blood transfusions, the traditional therapy, provides a quick solution but is associated with complications. This was the rationale for recombinant human Epo (rHuEpo) in the treatment of anemia of cancer. Over the past few years, about 20 publications have reported the results of rHuEpo in the treatment of cancer-associated anemia in more than 850 patients with a variety of malignancies. In general, more than half of the patients responded with a significant increase in their hemoglobin level, a decrease in blood transfusion requirements, and an improved performance status and quality of life. About 4 weeks are required till the onset of effect. The hormone is well tolerated with minimal adverse effects and subcutaneous injections appear to be the preferred method of administration. Additional studies will hopefully answer several questions including optimal dosage and duration of treatment, Epo resistance, and the possibility of predicting the response.     

Thickened gastric mucosal capillary wall: a histological marker for portal hypertension

We investigated the efficacy and safety of subcutaneous recombinant human erythropoietin (rHuEpo) in 25 children with chronic renal allograft dysfunction (13 girls, 12 boys, mean age 15.8 +/- 4.2 years) for a treatment period of 9-162 (median 43) weeks. rHuEpo was started once weekly at a dose of 105 +/- 25 U/kg per week in 16 children, twice weekly at a dose of 175 +/- 70 U/kg per week in 6 children, and three times weekly at a dose of 270 +/- 28 U/kg per week in 3 children. The hematocrit increased in 21 children from 23.2% +/- 3.1% to 33% +/- 3.1% within 7.2 +/- 4.9 weeks at a mean rate of 1.98%/week. The hematocrit increase and rHuEpo starting dose were linearly related (delta hematocrit/week = 0.8+0.08 U/kg per week, r = 0.44, P < 0.05). The maintenance dose was 74 +/- 23 (43-114) U/kg per week. Four children failed to reach the target hematocrit, most likely due to noncompliance. Seventeen recurrences of anemia ("anemic episodes") during rHuEpo therapy were identified in 12 children, mostly associated with acute or insidious deteriorations in graft function. There was no acceleration of progression of graft dysfunction with rHuEpo treatment. We conclude that subcutaneous rHuEpo at a single weekly dose of 100 IU/kg per week is highly effective in children with chronic graft dysfunction. Children who appear to be rHuEpo resistant or experience rHuEpo-resistant episodes should be assessed for noncompliance, changes in graft function since the last dosage adjustment, and blood loss, such as seen in dysfunctional uterine bleeding in adolescent girls.     

Sensitivity and specificity of transferrin saturation and serum ferritin as markers of iron status after intravenous iron dextran in hemodialysis patients

This study was designed to investigate the effect of intravenous (i.v.) iron dextran (i.d.) on hematocrit (Hct), transferrin saturation (TS), and serum ferritin (SF) in hemodialysis patients treated with a constant dose of erythropoietin (EPO). The sensitivity, specificity, and predictive values of SF and TS for monitoring i.d. therapy were also assessed. All hemodialysis patients with baseline SF < 100 ng/mL or TS < 20%, with EPO dose unchanged 6 weeks before and 4 weeks after dosing with i.d. were included. I.d. (500 mg-1 g) was given as an infusion over 1 h. Patients receiving packed RBC or with active bleeding were excluded. Hct, TS, and SF were measured 2 weeks before and 4 weeks after i.d. Linear correlation coefficients between dose of i.d., changes in Hct, TS, and SF were calculated. The sensitivity, specificity, and predictive values of TS and SF were compared. A positive Hct response was defined as a > 5% increase from baseline 4 weeks after administration of i.d. Thirty-three patients (17 females) received a total of 51 doses of i.d. Mean +/- SD i.d. dose was 770 +/- 278 mg. Hct increased by a mean +/- SD of 4.8% +/- 9.9% (33.4% +/- 3.0% to 34.9% +/- 4.1% [p = 0.028]); SF rose by a median of 208.65% (mean +/- SD of 126.8 +/- 132.1 ng/mL to 325.3 +/- 222.0 ng/mL [p < 0.0001]; TS increased by a median of 53.8% (19.4% +/- 9.4% to 29.3% +/- 11.3% [p < 0.0001]) from baseline values. The correlations between dose of ID and percent changes in SF, TS, and Hct were poor (r2 < 0.02). The sensitivities and specificities were 74% and 36% (TS < 20% alone); 60% and 30% (SF < 100 ng/mL alone); and 33% and 67% (TS < 20% and SF < 100 ng/mL), respectively. The predictive values for positive responses were 48% for TS and 45% for SF when used alone, and 47% when both indices were used together. The predictive value increased to 65% when either SF < 100 ng/mL or TS < 20% were used. At a constant EPO dose, there was a statistically significant increase in Hct 4 weeks after i.d. administration in patients who were diagnosed with iron deficiency by using TS < 20% or SF < 100 ng/mL. The dose of i.d. administered was poorly correlated to changes in Hct, TS, and SF. Both TS and SF are non-specific and insensitive indicators for accurate diagnosis of iron deficiency in hemodialysis patients in EPO.