Sickle cell disease (SCD) is a genetic disease that afflicts over eighty thousand Americans, 4 to 5,000 newborns per year in the US, and 100s of thousands of children and adults world-wide. This disease arises from a single amino acid mutation of the beta globin chain of hemoglobin, which results in abnormal polymerization of deoxygenated hemoglobin. The deceptively simple biologic origin for SCD belies the debilitating chronic multi-faceted clinical syndrome with which it is associated;SCD is characterized by lifelong hemolysis, chronic anemia, recurrent painful vaso-occlusive crises (VOC), hepatic, renal, musculo-skeletal, and central nervous system complications, and a shortened life-expectancy. Our group has found an up to 33% incidence of pulmonary hypertension in adult patients with SCD who were screened and followed prospectively;with two-year follow-up, this pulmonary hypertension is associated with a 10-fold increased mortality rate. Hydroxyurea has emerged as a useful therapy in sickle cell disease. It is a cell-cycle specific agent that blocks DNA synthesis by inhibiting ribonucleotidereductase, the enzyme that converts ribonucleotides to deoxyribonucleotides. Hydroxyurea has been shown to induce the production of fetal hemoglobin (HbF) in patients with sickle cell anemia, with associated diminished morbidity and, likely, mortality in these patients. Any HbF is good in SCD, although it is estimated that levels of 20 percent HbF are required to substantially reduce the sickling propensity of red cells and to modulate disease severity. The majority of patients with SCD respond to hydroxyurea with a more than two-fold increase in HbF levels;in some patients the percent of HbF exceeds 10 or 15 percent, but it is not uniformly distributed in all cells, i.e. has a hetero-cellular rather than a pan-cellular distribution. The mechanism through which hydroxyurea augments fetal Hgb is incompletely characterized. An additional benefit of hydroxyurea may be through effects on the nitric oxide (NO) system. Recently, members of our group found that hydroxyurea therapy is associated with the intravascular and intra-erythrocytic generation of NO, and that NO increases HbF expression via the guanylyl cyclase/cGMP dependent pathways. We have treated more than 30 patients chronically with hydroxyurea to determine hematological changes Iongitudinally, and have established the maximal HbF raising effect of hydroxyurea in these patients. We have found that the levels of HbF that are induced by hydroxyurea alone are insufficient, and insufficiently widely distributed, to ameliorate the life-threatening complications of pulmonary HTN and of on-going hemolysis in patients with sickle cell disease. Earlier studies had suggested that the addition of erythropoietin (Erythropoietin) therapy to chronic hydroxyurea therapy may induce fetal hemoglobin at higher, more widely distributed, levels. We plan to test this in patients with sickle cell disease who have chronic kidney disease, which, presumably, leaves them with a depressed Erythropoietin reserve and an inability to tolerate standard doses of F-inducing therapy with hydroxyurea, and in patients with pulmonary HTN, which carries an ominous prognosis in SCD. A secondary endpoint of this study will be to evaluate if hydroxyurea plus Erythropoietin therapy can improve cardiovascular aerobic capacity in general, and in particular minimize symptoms and morbidity in patients with both chronic kidney disease and pulmonary HTN. We had planned to enroll up to 60 males or females, age 18 and above with sickle cell disease. We began enrollment in June 2006 and enrolled a total of seven subjects. Of those 7 subjects, 2 completed the study, 2 were dropped due to Serious Adverse Events, 2 were dropped due to non-compliance, and 1 was dropped due to an inability to tolerate the entry level hydroxyurea dose over the course of the study. The study was closed to enrollment on June 3, 2008. Five patients received HU and EPO, per protocol. Complete data are available for four patients, and final complete data are being collected for the 5th patient. Total hemoglobin rose in 5/5 patients (p<.05), total fetal hemoglobin rose in 2/4 patients, and dropped in 2/4 patients (p<.05 from baseline for each). LDH rose in 4/4 patients (p<.05 from baseline). Suprapharmacologic EPO increases total Hgb in all patients, and may increase HbF in some patients, but this is accompanied by evidence for increased hemolysis. Data from this small study suggests that supratherapeutic doses of erythropoietin will increase total hemoglobin and may increase fetal hemoglobin in some patients with sickle cell disease. However, all patients show evidence for increased hemolysis. Final data are being accumulated from the 5th patient, and a manuscript has been published. The following summary is adapted from the abstract: Erythropoietin is being used more widely in the management of sickle cell disease (SCD, inclusive of homozygous sickle beta, SS, and compound heterozygous sickle beta thalassemia, Sbeta0 thal), often in conjunction with hydroxyurea (HU). Herein, we summarize the published experience with erythropoietin use in SCD, in 39 patients (SS, n = 30;Sb0 thal, n = 9) who were treated between 1990 and 1996;and in 13 patients with sickle syndromes (SS, n = 12, compound heterozygous SC disease, n = 1) who were treated with erythropoietin or darbepoietin at the National Institutes of Health (NIH) since 2002. The dose range of erythropoietin for SCD in the published series, at a median of >200 U/Kg/dose, is higher than that used in end-stage renal disease. The median duration of erythropoietin therapy was >or =3 months, with minimal reported side-effects. At the NIH, the median age of sickle syndrome patients who received erythropoietin or darbepoietin (both referred to as EPO in the NIH series) was 51 (24 to 70) years;12/13 patients had sickle-associated pulmonary hypertension. Eleven out of the 13 patients were treated with both HU and EPO for >4 months (median of 11 months on EPO) without complication. Of the 13 patients, five (all SS) with pulmonary hypertension were given EPO for reticulocytopenia (<100,000/mL) on HU;5/13 patients (all SS), with pulmonary hypertension, were given EPO and HU concurrently, in the light of an estimated glomerular filtration rate of <80 mL/minute. Three of the 13 patients (2 SS, 1 SC) were treated with EPO for miscellaneous reasons. Hematologic responses, detailed herein, suggest that EPO therapy may allow more aggressive HU dosing in high-risk SCD patients and in the setting of mild renal insufficiency, common to the aging sickle cell population. Furthermore EPO appears to be safe in SCD, particularly when used in conjunction with HU. No new subjects will be enrolled and no study medication will be administered. However, we intend to use blood samples collected under this protocol to compare the subjects enrolled in this study who all had renal insufficiency with sickle cell subjects who do not have renal insufficiency and are currently enrolled on our Blood Draw study 03-CC-0015. We will look for vaso-active substances that are differentially regulated in chronic kidney disease compared to subjects with more normal kidney function in sickle cell disease to determine if renally cleared substances contribute to underlying pathogenesis in sickle cell disease. We are also using frozen samples to measure placenta growth factor, endothelin-1 and other cytokines, growth factors, or protein markers of inflammation.
