Use Of rHuEPO Research Articles

Anemia management in patients with chronic renal insufficiency

The introduction of recombinant human erythropoietin (rHuEPO) more than a decade ago provided the first effective treatment for the anemia of chronic renal insufficiency (CRI). The use of rHuEPO in the treatment of anemia has been associated with partial regression of left ventricular hypertrophy among both dialysis and nondialysis patients, and has been shown to reduce the frequency of cardiac complications such as congestive heart failure and number of days of hospitalization among dialysis patients. Despite this evidence, the anemia of CRI remains highly prevalent, underrecognized, and undertreated. A number of considerations arise regarding the management of anemia among patients with CRI. In this article, we review the rationale for treatment of anemia, current management practices, proposed treatment strategies, and the economic implications of improved anemia treatment.

Use of Erythropoietin and Its Effects on Blood Lactate and 2,3-Diphosphoglycerate in Premature Neonates

The aim of this study was to investigate the effect of recombinant human erythropoietin (rHu-EPO) on oxygen affinity and adequate oxygen delivery to the tissues of stable premature infants. 36 very-low-birth-weight infants were randomly assigned to either receive rHu-EPO (200 units/kg every other day) or not, and both groups were supplemented with iron, folic acid and vitamin E. Arterial blood gases, oxygen saturation, complete blood counts, fetal haemoglobin, 2,3-diphosphoglycerate (2,3-DPG) and blood lactate were analysed weekly, from the 1st week till discharge. Patients in the two groups were comparable. There was a trend in increasing lactate values towards the 4th to 5th weeks of life, which did not reach statistical significance. There was no correlation between lactate values and the studied variables (pH, BE, oxygen saturation). In 35 transfusions, pre- and 24 h post-transfusion blood lactate status was studied. In 23 of them, a decrease in post-transfusion lactate was noticed, whilst an increased post-transfusion level was shown in 10 cases and no change in 2 cases. The mean pre-transfusion lactate value was significantly higher than the post-transfusion one (24.04 ± 11.9 mg/dl before and 16.27 ± 8.5 mg/dl after transfusion; p = 0.0025). In both groups there was a steady rise in 2,3-DPG concentration over the period of study, and the 2,3-DPG values at the end of our study were significantly increased in the rHu-EPO group (rHu-EPO 5.98 ± 0.9, control 4.84 ± 0.7; p = 0.04). In conclusion, the use of rHu-EPO did not affect blood lactate levels compared to the control group. Regarding oxygen affinity, it seems that rHu-EPO causes a shift of the oxy-haemoglobin dissociation curve to the right. This is a previously unreported effect of rHu-EPO and its clinical use may, thus, confer to preterm babies an added advantage.

PII: S0003-4975(99)00840-1

Doctor Kiyama and colleagues add to the evidence that preoperative recombinant erythropoietin (RHuEPO) and oral iron therapy effectively reduces the need for red blood cell transfusion during cardiac operations. Their patient population with anemia and small stature (body surface area, ≈1.5 m2) selects for the ideal candidates for RHuEPO therapy, that is, those coming to operation with reduced red cell mass. They demonstrate that red cell enhancement has a separate effectiveness profile from blood loss reduction (aprotinin). Furthermore, their work suggests that aprotinin may not be important in patients with red cell mass deficiency and no risk factors for bleeding. They do not answer several important questions. Is the addition of preoperative autologous blood harvest to RHuEPO/iron necessary? There is evidence that allowing patients to bank their own blood intravascularly works just as well, with less invasiveness and cost. Each autologous cell harvest in Dr Kiyama’s study involved significant costs: harvest and handling, a laboratory test, and a nonstandard harvest goal that had to be adjusted based on the results of the laboratory test. Allowing the red cell mass to increase without harvesting eliminates these costs. Of course the safety of forcing a rapid preoperative red cell mass increase in cardiac surgical patients remains to be compared with the safety of multiple preoperative blood donations. The primary safety outcome, perioperative death, remains inadequately addressed in this study. Our multicenter experience with RHuEPO in cardiac surgical patients demonstrated a nonsignificant increase in death during a 6-month perioperative period in the erythropoietin-treated group versus placebo. Statistical nonsignificance notwithstanding, the Food and Drug Administration has consequently required the drug to be labeled as “not indicated in cardiac and vascular surgery.” It would be useful if future studies of RHuEPO report not only operative, but also perioperative death. Perhaps outcome databases such as The Society of Thoracic Surgeons database could include a field for preoperative RHuEPO use to further address this most important safety question.

What are cancer patients willing to pay for prophylactic epoetin alfa?—A cost‐benefit analysis

The article by Ortega et al. provided further evidence to consider regarding recombinant human erythropoietin (r-HuEPO) use in the treatment of cancer patients.1 They addressed the economic aspects of r-HuEPO in cancer-related anemia and described the patients' perspective regarding the use of an expensive technology for their treatment. As the expensive drugs provided by high technologies gain wider areas of application, it seems that this discussion will be more popular among clinicians, patients, and health care providers who are supposed to pay for r-HuEPO. We believe the use of r-HuEPO, which is an expensive drug, will become wider in the near future, as is usually the case with high technology drugs that give the patient more comfort for higher cost. At this point, we have to stress the clinicians' responsibility for defining more clear-cut outlines of the therapeutic aspects of the drug in terms of cost-benefit advantage. In the case of r-HuEPO, this is quite complex. r-HuEPO is not simply a supplementary drug for cancer anemia. It is an endogenously secreted hormone that affects many systems. Chemotherapeutic agents may alter the endogenous secretion of EPO and may cause an EPO-resistant state.2, 3 High EPO levels after a renal injury and enhancement of recovery from cisplatin-induced acute renal failure have been shown, perhaps reflecting the role of EPO as part of the endogenous defense mechanism of the kidney.4, 5 The protective effect of EPO against neuronal damage is also under investigation.6, 7 These points need further investigation and must be considered in determining the potential therapeutic benefits of r-HuEPO therapy (especially for patients receiving cisplatin-based combinations that are potentially nephrotoxic and neurotoxic, because these side effects are being considered as important dose-limiting factors in clinical use). In this complexity, the clinicians' responsibility starts with investigating the benefits of r-HuEPO and identifying the patient population that will benefit most from the use of this drug. There is no consensus on the administration of this drug to cancer patients for reduction of transfusion requirements or for quality of life, whether the patient is receiving cytotoxic chemotherapy or not, although most studies point out the benefits.8-12 To determine the patient group that will benefit most from the use of this drug, we must first identify the patients who have the least tolerance of the complications of anemia and blood transfusions (i.e., older patients, who usually have a diminished reserve, and patients with underlying renal, pulmonary, and cardiovascular diseases). A history of previous cytotoxic treatment and frequent transfusions may also be important indicators; and rare blood groups, which are considered less often, must be regarded as important factors in patient selection for treatment with r-HuEPO. After determination of the patient group that is most prone to the complications of anemia and transfusion, we have to identify further the subsets of patients who will benefit from the treatment. These patients have low levels of endogenous EPO and have normal baseline leukocyte and platelet counts, indicating adequate bone marrow reserve. The criteria for the response to treatment have been defined previously and include increases in hemoglobin level more than 0.5 g/dL after 2 weeks, soluble transferrin receptor level after 2 weeks, and reticulocyte count after 4 weeks of r-HuEPO treatment.8, 13, 14 Another important issue is the dose: 150 U/kg 3 times a week seems to be an appropriate dose for patients not receiving cytotoxic chemotherapy.8 Patients treated with cytotoxic agents, especially cisplatin, seem to need higher doses.8, 15 Starting with the dose of 150 U/kg 3 times a week, and then doubling the dose after 2 weeks of therapy if there is not a response, seems to be an appropriate approach; still, dose schedule remains a subject of intensive research.8, 9, 11, 13, 14 We think this is the clinicians' strategy for extracting and treating the patients who will benefit most from r-HuEPO therapy. However, at this point, what we have learned from Ortega et al is to determine the willingness of the patient to receive a therapy for the correction or prevention of anemia at the expense of frequent injections, side effects such as hypertension, increased frequency of thrombotic events, high cost, and considerable incidence of treatment failure, instead of receiving blood products for the symptomatic management of anemia. Bülent Orhan M. D.*, Şuayib Yalçin M. D. , * Department of Medical Oncology, Uludag University School of Medicine, Bursa, Turkey, Department of Medical Oncology, Hacettepe University Institute of Oncology, Bursa, Turkey

Erythropoietin and preoperative autologous blood donation in the prevention of hepatitis C infection: necessity or luxury?

Prevention of exposure to allogeneic blood transfusion during surgery is an important financial issue when recombinant human erythropoietin (rHuEPO) is used in addition to preoperative blood donation. The aim of this study was to carry out a cost-effectiveness analysis of the use of rHuEPO in preoperative blood donation in orthopedic surgery. The study, based on a decision tree analysis of the use of rHuEPO, was conducted from the perspective of the French health care system. The efficacy criterion was the number of hepatitis C infections prevented. The decision tree analysis was constructed as follows: the residual risk of hepatitis C infection was 8.26 per million units transfused, and the chance node was defined according to the number of units transfused. With the use of rHuEPO in preoperative blood donation, 0.30562 cases of hepatitis C infection per 100,000 patients were prevented. The incremental cost of one prevented hepatitis C infection amounted to $888,000,000 (US). Despite the limitations of our model, the cost-effectiveness ratio was so large that variations only slightly modified the size of the result. From the societal perspective, it was not cost-effective to add rHuEPO to preoperative blood donation.

Erythropoietin treatment for non-uremic patients:: a personal view

The correction of anemia in patients with chronic renal failure (CRF) has become the most important application of recombinant human erythropoietin (rHuEpo). The merits of rHuEpo therapy in patients with CRF are overt. Firstly, patients with CRF have an absolute deficiency in endogenous erythropoietin production and a relatively low maintenance dose of rHuEpo (often less than 100 IU/kg body weight per week) is effective in avoiding regular transfusions in the majority of the patients with CRF. Secondly, rHuEpo is able to avoid long-term complications of frequent transfusions (hemochromatosis, transfusion-transmissible diseases). Thirdly, patients with uremia notice a considerable improvement in quality of life (QOL) after initiation of rHuEpo. These advantages justify administration of this costly drug in CRF patients.The use of rHuEpo outside the setting of uremia do, however, not cover the complete spectrum of beneficial effects as compared to its use in (pre)dialysis patients. The aim of this overview is to provide some annotations on recently approved (cisplatin-induced anemia, preoperative anemia, zidovudine-related anemia) and possibly future (several types of malignancy and inflammation) indications for rHuEpo in non-uremic patients, leaving out the correction of anemia due to relatively uncommon disorders in the Dutch population (such as sickle cell anemia and thalassemia).

The utility of a growth factor: r-HuEPO as a treatment for preoperative autologous blood donation in gynecological tumor surgery.

The use of r-HuEPO and sodium ferrous gluconate has been shown to be a safe and effective treatment which can be used by transfusional centers and surgeons to avoid allogeneic blood transfusions and to schedule short-term selective surgery. In this study the authors submitted 20 patients scheduled to undergo surgery for gynecological tumors to a program of pre-operative autologous blood donation. All the patients received both r-HuEPO and sodium ferrous gluconate in the pre- and post-donation period. r-HuEPO was administered subcutaneously in a dose of 200 IU/kg thrice weekly during the week before and after autologous blood donation (400 ml). Sodium ferrous gluconate was administered intravenously shortly before the first and fourth administration of 125 mg of r-HuEPO. Surgery was scheduled to be performed 10-15 days after the last r-HuEPo administration, i.e. within 15-20 days from blood donation. All the patients were tested for the following blood chemistry parameters: hematocrit, hemoglobin, sideremia and ferritin at treatment start, prior to donation, at treatment end, prior to autologous blood infusion and on the third and seventh day after surgery. No patient receiving r-HuEPO required allogeneic blood transfusion as both the hematocrit and hemoglobin values remained normal. r-HuEPO was observed to be a safe and effective treatment to be used in autologous blood donation programs in all patients scheduled to undergo surgery. It limits the decrease of hematocrit values following autologous blood donation thus enabling all the patients who for a variety of reasons to refuse allogeneic blood infusion to predeposit autologus blood shortly before the date scheduled for surgery.

Blood transfusion in oncologic surgery: the role of recombinant human erythropoietin (rHuEPO)

Anemia is common in cancer patients. The pathophysiology is multifactorial, however the most common cause is the anemia of chronic diseases (ACD). In 20-50% of cancer patients, anemia restricts physical activity and quality of life and requires transfusion support. The percentage of patients necessitating transfusion dramatically increases when patients require surgery. The traditional belief that blood transfusion is an effective and safe therapy has been challenged by a heightened awareness of the infectious and immunologic risks associated with allogeneic blood administration. In cancer patients transfusion-induced immunomodulation may have the potential to significantly increase postoperative infections and cancer recurrence so that it seems reasonable to minimize allogeneic blood exposure. Several strategies have been adopted to reduce allogeneic transfusion in surgical patients, however to properly select the appropriate blood conservation strategies the blood transfusion requirements for each patient should be defined. Allogeneic blood transfusion in surgery can be reduced by the introduction of autologous blood (AB) programmes and by the use of rHuEPO, alone or in association with AB techniques. AB donation is currently a standard of care for elective surgical patients but its efficacy is limited by anemia that prevents the donation of the optimal number of AB units. rHuEPO has been shown to significantly increase the volume of AB that anemic patients can predeposit or, used perisurgically, to expand the circulating RBCs mass before surgery. Moreover clinical trials employed rHuEPO in anemic cancer patients with various solid tumors both on and off chemotherapy reporting a significantly increase in Hct in more than 50% of the treated patients. Recently different studies have shown the efficacy of rHuEPO in increasing the volume of AB also in patients with ACD and cancer, thus proving to be a useful addition to existing strategies of blood conservation to minimize exposure to allogeneic blood in surgical cancer patients.

Cost-effectiveness of recombinant human erythropoietin in the prevention of chemotherapy-induced anaemia.

Recombinant human erythropoietin (rHuEPO) has been advocated for the treatment of anaemia in patients submitted to cancer chemotherapy. We used decision analysis to compare the cost-effectiveness of rHuEPO supplemented with red blood cell (RBC) transfusions with conventional treatment with RBC transfusions alone. At baseline, we analysed the use of rHuEPO as secondary prophylaxis according to effectiveness estimates from a community-based oncology study. In order to reduce the probability of transfusions from 21.9% to 10.4%, and the number of RBC units per patient per month from 0.55 to 0.29, 150 units kg(-1) s.c. rHuEPO three times per week for 4 months resulted in an incremental cost of $189,652 per quality-adjusted life year (QALY). In patients treated with cisplatin-containing chemotherapy, rHuEPO added $190,142 per QALY. In a hypothetical scenario of a transfusion pattern that maintained the same haemoglobin level of rHuEPO-responsive patients, the marginal cost of rHuEPO was always greater than $100,000 per QALY. Results were stable with regard to variations in the probability of blood-borne infections, quality of life of responding patients and cancer-related mortality. The additional cost could be lowered to less than $100,000 per QALY by saving 4.5 RBC units over 4 months for any patient treated. In conclusion, according to current use, rHuEPO is not cost-effective in the treatment of chemotherapy-induced anaemia. More tailored utilization of the drug and better consideration of predictive response indicators may lead to an effective, blood-sparing alternative.

Benefits and concerns of treating pre-dialysis and renal transplant patients with recombinant human erythropoietin.

The possibility of lower efficacy and the fear of an increased incidence of side effects may explain the reluctance to use recombinant human erythropoietin (r-HuEPO) in patients with impaired renal function who do not yet require dialysis, as well as in transplanted patients with a failing renal allograft. Several recent studies have clearly shown that r-HuEPO is effective in these patient populations and that the doses needed to control anaemia are comparable with or lower than those needed for dialysis patients. When started at a low dose, the risk of severe hypertension is minimal, although in a significant number of patients intensification of the antihypertensive regimen is needed. Moreover, there are no indications that the use of r-HuEPO accelerates the deterioration of residual renal function.

Recombinant human erythropoietin: 10 years of clinical experience.

The need for a renewable source of erythropoietin to treat the anaemia of chronic renal failure was first recognized in the 1960s, but cloning and expression of the human gene was not achieved until 1983. Clinical testing of recombinant human erythropoietin (r-HuEPO) began in 1985, leading to the first licence as a therapeutic agent in 1988. The first clinical trials showed that an intravenous dose requirement of about 200 IU/kg/week would increase haemoglobin concentrations to 10-12g/dl in >90% of haemodialysis patients. Subcutaneous administration has subsequently been found to be effective, and may allow lower maintenance doses. It is now the route of choice in Europe, but not the USA. The best marker of benefit of the introduction of r-HuEPO is the reduction in need for regular blood transfusions. A marked improvement in anaemia-related symptoms has been clearly demonstrated. The most important factor in optimizing the response to r-HuEPO is iron supply. The marrow should be stimulated slowly, to allow mobilization of iron stores. Functional or absolute iron deficiency should be pre-empted by regular iron supplementation. It is also important to recognize resistant states induced by inflammation and bleeding, and to exclude severe hyperparathyroidism, aluminium overload and other haematological diseases. The most important adverse events associated with r-HuEPO are increased blood pressure and a possible increased risk of access failure. These are, however, challenges to improve practice, not reasons to avoid the use of r-HuEPO.

Use of recombinant human erythropoietin for management of anemia in dogs and cats with renal failure

Objective To test efficacy and safety of recombinant human erythropoietin (r-HuEPO) administration in dogs and cats with naturally developing chronic renal failure. Design Case series. Animals 6 client-owned dogs and 11 client-owned cats with chronic renal failure. Procedures r-HuEPO was administered intravenously or subcutaneously. Erythropoietic effects were monitored by determining CBC, performing cytologic examination of bone marrow aspirates, and measuring serum iron concentration before and during treatment. Development of adverse effects was monitored by performing sequential clinical assessments, CBC, and serum biochemical tests and by measuring indirect blood pressure and anti-r-HuEPO antibody titers. Results Administration of r-HuEPO increased RBC and reticulocyte counts, hemoglobin concentration, and Hct comparably in dogs and cats. Assessments of clinical well-being, including appetite, energy, weight gain, alertness, strength, and playfulness, were improved variably. Adverse effects, including anemia, anti-r-HuEPO antibody production, seizures, systemic hypertension, and iron deficiency, were demonstrated inconsistently in dogs and cats. Clinical Implications Anemia contributes to clinical manifestations of chronic renal failure in dogs and cats. Administration of r-HuEPO has the potential to resolve anemia and improve clinical well-being. However, its administration poses risks of antibody production and adverse effects associated with correction of RBC mass. Use of r-HuEPO in dogs and cats requires conscientious assessment of risks and benefits until homologous forms of erythropoietin are available. (J Am Vet Med Assoc 1998; 212:521-528)

Secular trends in recombinant erythropoietin therapy among the U.S. hemodialysis population: 1990–1996

Chronic anemia is a major cause of morbidity among the end-stage renal disease (ESRD) population. Recombinant erythropoietin (rHuEPO) has been recognized as a major advance in the treatment of anemia among the ESRD population. This study examines the secular trends in the use of and response to rHuEPO therapy among severely, moderately and mildly anemic hemodialysis patients. We designed a cohort analytic study using seven years of claims data. The study population comprised all facility-based adult hemodialysis patients receiving rHuEPO therapy, who were initially reimbursed by Medicare in each of the first quarter of the calendar years 1990 through 1996 (N = 64,957). Between 1990 and 1996, the mean rHuEPO dose increased by 139% for the patient cohorts with a first observed hematocrit < 0.25, 122% for the 0.25 to 0.29 cohorts, and 107% for the > or = 0.30 cohorts, and produced a 0.02 to 0.03 increase in achieved hematocrit (A-Hct) over this time. Dosing of rHuEPO did not appear to be influenced by patient or provider characteristics, although African-Americans, the elderly, non-diabetics and persons receiving dialysis in a non-profit facility had a larger percent change in hematocrit compared to their counterparts (P < 0.001). The results of the clinical use of rHuEPO seven years after FDA approval found in the general ESRD hemodialysis population have not equaled the results obtained in the initial clinical trials. Overall, our findings suggest that substantial increases in rHuEPO dose provided to anemic patients have resulted in only modest increases in hematocrit in the seven years since rHuEPO's introduction. Resistance to rHuEPO, prior rHuEPO treatment, inadequate use of supplemental iron, and policy and financial incentives may explain this finding.

Management of chemotherapy-related anaemia with low-dose recombinant human erythropoietin in patients with small cell lung cancer.

We examined the efficacy of low-dose erythropoietin in the management of chemotherapy-related anaemia in patients with small cell lung cancer (SCLC). We gave recombinant human erythropoietin A (rHuEPO) to 63 SCLC patients, 30 with limited disease (LD) and 33 with extensive disease (ED) who underwent chemotherapy with carboplatin, etoposide and ifosfamide and had previously received blood transfusions for chemotherapy-related anaemia. rHuEPO was given at a dose of 2000 IU subcutaneously three times per week for 2 weeks after every chemotherapy cycle, starting 48 h after the end of chemotherapy. Before the use of rHuEPO, all patients in both groups had to be transfused after a mean of 5.5 CT cycles. In 64 CT cycles following administration of rHuEPO, only 5/30 LD patients (17%) had to be transfused in six cycles (9%). In 88 cycles following the use of rHuEPO, 7/33 ED patients (21%) had to be transfused in 11 cycles (12.5%). Haemoglobin values in patients with ED (but not those with LD) were significantly improved after rHuEPO administration on both day 14 and day 28 after chemotherapy. No adverse effects were recorded. rHuEPO considerably decreased the degree of anaemia and the need for blood transfusion at doses markedly lower (25-30 IU/kg body weight) than those reported in the literature so far (150 IU/kg body weight), without toxicity.

Anaemia of prematurity. Epidemiology, management and costs.

Recombinant human erythropoietin (rHuEpo) has been increasingly used in preterm infants in the last 3 to 4 years. Recent studies have indicated a reduction in blood transfusion requirements in infants receiving rHuEpo. No significant adverse effects have emerged, apart from iron deficiency (if iron supplementation is inadequate), and the risk of transfusion-related infection is decreased. Nevertheless, rHuEpo is relatively expensive (a 6-week course costs approximately the same as 2 blood transfusions), so its use requires careful consideration; it is logical to target rHuEpo therapy to those babies who are most likely to be transfused. Using this strategy, 1 study involving stable growing preterm infants has shown that direct costs of blood transfusion and rHuEpo were similar, and the use of rHuEpo was recommended. In addition, use of high-dosage rHuEpo early in the course of management on the neonatal intensive care unit has been shown to reduce direct treatment costs in ill preterm infants. Further studies will continue to identify infants who are likely to benefit from rHuEpo therapy and to define its cost effectiveness in more detail.

Maternal and Perinatal Implications of the Use of Human Recombinant Erythropoietin

Background. The use of human recombinant erythropoietin (rHuEPO) in pregnant patients has been limited by the fear of eventual maternal and fetal repercussions (either direct or indirect).Methods. The authors present their experience with the use of rHuEPO during pregnancy, with two pregnant women with kidney transplants and in three others with chronic renal insufficiency (one with diabetic nephropathy, another dialysis dependent), all with hematocrit below 30% and adequate iron reserves.Results. Three of the patients had needed blood transfusions before beginning therapy, and another needed transfusion after significant metrorrhagia. The length of the treatment varied between 2 and 23 weeks and the hematocrit at delivery varied between 26% and 36%. Secondary effects (appearance or worsening of hypertension and seizures) were nil. There was one fetal death at 23 weeks of pregnancy (following an abruptio placentce), two neonates weighing between the 5th and the 10th percentiles, and three needing photothe...

Angiotensin I converting enzyme inhibitor and worsening of anemia in hemodialysis patients: Prevention with rHuEPO.

Angiotensin I converting enzyme inhibitor (ACEI) is known to worsen anemia in hemodialysis (HD) patients. The effect of rHuEPO on ACEI-induced worsening of anemia was evaluated in 19 hypertensive HD patients. Patients were subdivided into two groups according to rHuEPO administration, being rHuEPO (+) group (n=10, 56±4 years old, rHuEPO 1500 units, 3 times a week) and rHuEPO (-) group (n=9, 52±3 years old). Age, HD duration, blood pressure (BP) and hematocrit (Ht) before ACEI (lisinopril) were not significantly different between rHuEPO (+) and rHuEPO (-) group. Lisinopril was started with a dose of 2.5mg once a day in the morning on non-HD day. BP decreased significantly in both groups and adequately maintained throughout the study period. Ht decreased significantly in rHuEPO (-) group from 30±2 to 26±1% (p<0.05), whereas it remained unchanged in rHuEPO (+) group. The dose of lisinopril of 5.0±2.0mg/day in rHuEPO (+) group was significantly higher than that of 3.0±1.0mg/day in rHuEPO (-) group (p<0.05). Serum erythropoietin and plasma angiotensin II concentration decreased but the changes were not significant in both groups. Plasma angiotensin I converting enzyme activity decreased significantly from 51±5 to 30±4U/L only in rHuEPO (-) group (p<0.05). In conclusion, we suggest that the ACEI-induced worsening of anemia could be prevented by a concomitant use of rHuEPO in hypertensive HD patients. However, the higher dose of ACEI was required to control BP in rHuEPO-treated HD patients.

The effects of recombinant human erythropoietin on growth and nutritional status.

The availability of recombinant human erythropoietin (rhuEPO) has dramatically improved the care of children with chronic renal failure (CRF). Its use provides the opportunity to determine the relative contribution of anemia to the morbidity of CRF. Growth retardation, one of the most significant complications of CRF in children, is the consequence of several inter-related processes, including decreased protein and energy intake, metabolic bone disease, endocrine abnormalities, and anemia. The literature on the use of rhuEPO in children and data from a United States phase III double-blind, placebo-controlled study of rhuEPO in pediatric dialysis patients are reviewed to determine the effect of rhuEPO treatment on the nutritional status and growth of children with CRF. Despite subjective increases in appetite, there were no consistent improvements in dietary intake or anthropometric measures observed during rhuEPO treatment. Children gained weight during rhuEPO treatment; however, this was not generally associated with increased weight standard deviation scores. There was an improvement in growth velocity in some children; however, improvements in height standard deviation scores were infrequently seen. On review of the available literature, correction of anemia with rhuEPO has not been shown to improve the growth of children with CRF.

Maternal and perinatal implications of the use of human recombinant erythropoietin.

The use of human recombinant erythropoietin (rHuEPO) in pregnant patients has been limited by the fear of eventual maternal and fetal repercussions (either direct or indirect). The authors present their experience with the use of rHuEPO during pregnancy, with two pregnant women with kidney transplants and in three others with chronic renal insufficiency (one with diabetic nephropathy, another dialysis dependent), all with hematocrit below 30% and adequate iron reserves. Three of the patients had needed blood transfusions before beginning therapy, and another needed transfusion after significant metrorrhagia. The length of the treatment varied between 2 and 23 weeks and the hematocrit at delivery varied between 26% and 36%. Secondary effects (appearance or worsening of hypertension and seizures) were nil. There was one fetal death at 23 weeks of pregnancy (following an abruptio placenta), two neonates weighing between the 5th and the 10th percentiles, and three needing phototherapy (1 to 2 days). One year after birth, all showed a normal ponderal and neurologic development. Among the cases presented, no maternal and perinatal complications attributable to rHuEPO were registered. It is important that institutions report their experiences with the use of rHuEPO, given its restrictive indications and the limited experience of each institution.

Combination Therapy of Erythropoietin, Hydroxyurea, and Clotrimazole in a P Thalassemic Mouse: A Model for Human Therapy

beta thalassemia (beta thal) in DBA/2J mice is a consequence of the spontaneous and complete deletion of the beta major globin gene. Homozygous beta thal mice have clinical and biological features similar to those observed in human beta thal intermedia. Erythrocytes in human beta thal are characterized by a relative cell dehydration and reduced K+ content. The role of this erythrocyte dehydration in the reduced erythrocyte survival, which typifies the disease, has not previously been evaluated. We examined for 1 month the effects on the anemia and the erythrocyte characteristics of beta thal mice of daily treatment with either clotrimazole (CLT), an inhibitor of red blood cell (RBC) dehydration via the Gardos channel, or human recombinant erythropoietin (r-HuEPO), or hydroxyurea (HU). The use of either r-HuEPO or HU induced a significant increase in hemoglobin (Hb), hematocrit (Hct), erythrocyte K+ and a decrease in percent reticulocytes, suggesting improved erythrocyte survival. CLT alone decreased only mean corpuscular hemoglobin concentration (MCHC) and cell density and increased cell K+. Thus, though the Gardos channel plays a major role in cell dehydration of murine beta thal erythrocyte survival. Combination therapy with r-HuEPO plus HU produced no incremental benefit beyond those of single drug therapy. However, addition of CLT to r-HuEPO, to HU, or to combined r-HuEPO plus HU led to statistically significant increase in Hb, Hct, and erythrocyte K+ compared with any of the regimens without CLT. These results suggest that CLT not only inhibits erythrocyte dehydration, but also potentiates the erythropoietic and cellular survival responses to r-HuEPO and HU.