Elevated Serum Erythropoietin Levels Research Articles

Suspected renal interstitial cell tumor causing polycythemia in two dogs.

Here we report a case series of two dogs diagnosed as renal interstitial cell tumor (RICT) accompanied by elevated serum erythropoietin level and marked polycythemia. RICT is a rare tumor in dogs, originating from renal interstitial cells. While several renal tumors such as renal lymphoma, adenocarcinoma, carcinoma, sarcoma, fibrosarcoma and nephroblastoma may cause polycythemia, polycythemia caused by RICT has never been reported in dogs. The tumors in both dogs were solitary and lied within cortex or cortico-medullary junction. Histopathology revealed spindle-shaped cells suggesting mesenchymal origin, with no mitotic figures suggesting that the tumors in both dogs were benign. Following surgical removal of the affected kidney, serum erythropoietin level and polycythemia normalized in both dogs.

Polycythemia Vera with Elevated Erythropoietin Level: A Review

According to the 2016 World Health Organization (WHO) recommendations, polycythemia vera (PV) should be suspected at hemoglobin levels of 16.5 gm/dl in males and 16 gm/dl in females. Depending on the underlying driving factor, polycythemia is classified to primary and secondary. Secondary polycythemia is driven by erythropoietin (EPO), which can be released due to hypoxemia, as seen in people living at high altitudes, those with chronic lung diseases, obstructive sleep apnea (OSA) and smoking. It can also be directly released by an underlying EPO secreting tumor, such as renal cell carcinoma. On the other hand, primary polycythemia or polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) in which erythrocytosis is driven by an acquired activating mutation that increases sensitivity to EPO or causes EPO independent erythroid colony formation. Manifestations of PV include fatigue, excessive itching, abdominal pain, weight loss, and fever. However, the most critical complications of PV, which impact survival, are thrombotic complications such as stroke and venous thromboembolism and leukemic transformation. The risk for leukemic transformation in patients with PV is about 2-5% over 15 years and is more common in individuals older than 60. History and physical examination should focus on smoking history and signs and symptoms of cardiopulmonary diseases causing chronic or intermittent hypoxemia, as seen in OSA. On the other hand, findings of abdominal pain, early satiety, weight loss, erythromelalgia, and hepatosplenomegaly would be suggestive of PV. Laboratory workup classically starts with measuring EPO level which further directs workup toward PV or secondary polycythemia. If workup is suggestive of PV, the following steps would be testing for activating Janus Kinase 2 (JAK2) mutation (V617F), which has a sensitivity of 97% for PV, and bone marrow biopsy which shows hypercellularity with trilineage growth (panmyelosis) in cases of PV. EPO measurement constitutes an essential step in polycythemia workup. It is widely accepted that elevated EPO levels are associated with secondary polycythemia; and suppressed EPO level was considered a criterion to diagnose PV, according to the WHO 2016 diagnostic criteria for PV. We conducted a systematic review searching the entity of PV with elevated EPO to study the clinical significance and outcomes. Our search yielded 4 cases summarized in Table 1. The cases were of three males and one female, with a mean age of 50. Two of them were healthy, with two with comorbid diseases, and as seen in the table; only one was a smoker. The most common symptom was headache, followed by erythromelalgia. Thrombotic phenomena happened in a single case in the form of Budd Chiari syndrome. Hepatosplenomegaly was found in a single case, and splenomegaly was found in two cases. The mean Hb level was 20.2 gm/dl, and the mean EPO level was 213. EPO is a glycoprotein hormone that is mainly produced by the kidneys. However, it is also produced in small amounts in the liver, spleen, bone marrow, lungs, and brain. The primary regulator of EPO production is the partial pressure of oxygen (PaO2). Multiple case reports and case series suggested an association between PV with elevated EPO and Budd Chiari Syndrome. Thumures et al. described four patients that were diagnosed with Budd Chiari Syndrome with elevated red cell mass and were found to have elevated serum erythropoietin levels. PV was confirmed with JAK2 mutation assay and bone marrow biopsy examination. It is speculated that liver hypoxia with subsequent hepatocyte injury and necrosis caused by Budd Chiari Syndrome leads to EPO level elevation. Accordingly, we assume that patients with PV and elevated EPO have some degree of organ injury that results in the release of EPO into circulation. This highlights the importance of a systematic approach in medicine, where signs and symptoms remain the cornerstone in diagnosis and where lab tests should be taken in their appropriate clinical context. Thus, we recommend testing for JAK2 mutation in the proper clinical scenario regardless of the EPO levels. It still remains to be clarified whether there are any prognostic importance of the elevated EPO level in these patients and whether it would alter the management.

Mild hypobaric hypoxia influences splenic proliferation during the later phase of stress erythropoiesis

Tissue trauma and hemorrhagic shock are common battlefield injuries that can induce hypoxia, inflammation, and/or anemia. Inflammation and hypoxia can initiate adaptive mechanisms, such as stress erythropoiesis in the spleen, to produce red blood cells and restore the oxygen supply. In a military context, mild hypobaric hypoxia-part of the environmental milieu during aeromedical evacuation or en route care-may influence adaptive mechanisms, such as stress erythropoiesis, and host defense. In the present study, healthy (control), muscle trauma, and polytrauma (muscle trauma and hemorrhagic shock) mice were exposed to normobaric normoxia or hypobaric hypoxia for ∼17.5 h to test the hypothesis that hypobaric hypoxia exposure influences splenic erythropoiesis and splenic inflammation after polytrauma. This hypothesis was partially supported. The polytrauma + hypobaric hypoxia group exhibited more splenic neutrophils, fewer total spleen cells, and fewer splenic proliferating cells than the polytrauma+normobaric normoxia group; however, no splenic erythroid cell differences were detected between the two polytrauma groups. We also compared splenic erythropoiesis and myeloid cell numbers among control, muscle trauma, and polytrauma groups. More reticulocytes at 1.7 days (40 h) post-trauma (dpt) and neutrophils at 4 dpt were produced in the muscle trauma mice than corresponding control mice. In contrast to muscle trauma, polytrauma led to a reduced red blood cell count and elevated serum erythropoietin levels at 1.7 dpt. There were more erythroid subsets and apoptotic reticulocytes in the polytrauma mice than muscle trauma mice at 4 and 8 dpt. At 14 dpt, the red blood cell count of the polytrauma + normobaric normoxia mice was 12% lower than that of the control + normobaric normoxia mice; however, no difference was observed between polytrauma + hypobaric hypoxia and control + hypobaric hypoxia mice. Our findings suggest muscle trauma alone induces stress erythropoiesis; in a polytrauma model, hypobaric hypoxia exposure may result in the dysregulation of splenic cells, requiring a treatment plan to ensure adequate immune functioning.

Polyglobulia in patients with hemangioblastomas is related to tumor size but not to serum erythropoietin

BackgroundHemangioblastomas are associated with elevated hemoglobin (Hb) levels (polyglobulia), which is associated with a higher risk for cerebral stroke, cardiac infarction and pulmonary embolism. The pathomechanism of polyglobulia remains unclear and different theories have been postulated. Among those are elevated serum erythropoietin (EPO) levels caused by secretion of the tumor or associated tumor cyst.MethodsTo elucidate the pathomechanism, we systematically investigated the relation between polyglobulia, serum EPO level, size of the solid tumor and associated cyst in hemangioblastomas. We prospectively evaluated hemoglobin and EPO levels in a series of 33 consecutive patients operated on hemangioblastomas in our center. We measured the size of the solid tumor and associated cyst in magnetic resonance imaging. Statistical evaluations were performed using the Fisher’s exact test and student’s t-test.ResultsAs a result five patients had elevated hemoglobin levels. Only one of these had an elevated serum EPO level. Of 26 patients with normal hemoglobin levels, 4 patients had elevated EPO levels.Patients with low or normal hemoglobin levels (84%) had an average tumor size of 0.8 cm3, which differed significantly from patients with elevated hemoglobin levels (16%), who had an average solid tumor size of 8.0 cm3 (p < 0.05). We did not observe a significant correlation between EPO levels or polyglobulia and associated cysts.ConclusionsWe therefore conclude that in contrast to previous case reports and interpretations, our data show no correlation between polyglobulia and EPO levels or associated cysts in patients with hemangioblastomas. In fact, it is the size of the solid tumor that correlates with polyglobulia.The study was retrospectively registered in the German Clinical Trial Registry on 10 July 2014; Trial registration: DRKS00006310.

THE COMBINATION OF α-LIPOIC ACID INTAKE WITH ECCENTRIC EXERCISE MODULATES ERYTHROPOIETIN RELEASE.

The generation of reactive nitrogen/oxygen species (RN/OS) represents an important mechanism in erythropoietin (EPO) expression and skeletal muscle adaptation to physical and metabolic stress. RN/OS generation can be modulated by intense exercise and nutrition supplements such as α-lipoic acid, which demonstrates both anti- and pro-oxidative action. The study was designed to show the changes in the haematological response through the combination of α-lipoic acid intake with running eccentric exercise. Sixteen healthy young males participated in the randomised and placebo-controlled study. The exercise trial involved a 90-min run followed by a 15-min eccentric phase at 65% VO2max (-10% gradient). It significantly increased serum concentrations of nitric oxide (NO), hydrogen peroxide (H2O2) and pro-oxidative products such as 8-isoprostanes (8-iso), lipid peroxides (LPO) and protein carbonyls (PC). α-Lipoic acid intake (Thiogamma: 1200 mg daily for 10 days prior to exercise) resulted in a 2-fold elevation of serum H2O2 concentration before exercise, but it prevented the generation of NO, 8-iso, LPO and PC at 20 min, 24 h, and 48 h after exercise. α-Lipoic acid also elevated serum EPO level, which highly correlated with NO/H2O2 ratio (r = 0.718, P < 0.01). Serum total creatine kinase (CK) activity, as a marker of muscle damage, reached a peak at 24 h after exercise (placebo 732 ± 207 IU · L-1, α-lipoic acid 481 ± 103 IU · L-1), and correlated with EPO (r = 0.478, P < 0.01) in the α-lipoic acid group. In conclusion, the intake of high α-lipoic acid modulates RN/OS generation, enhances EPO release and reduces muscle damage after running eccentric exercise.

Decreased "ineffective erythropoiesis" preserves polycythemia in mice under long-term hypoxia.

Hypoxia induces innumerable changes in humans and other animals, including an increase in peripheral red blood cells (polycythemia) caused by the activation of erythropoiesis mediated by increased erythropoietin (EPO) production. However, the elevation of EPO is limited and levels return to normal ranges under normoxia within 5-7 days of exposure to hypoxia, whereas polycythemia continues for as long as hypoxia persists. We investigated erythropoiesis in bone marrow and spleens from mouse models of long-term normobaric hypoxia (10 % O2) to clarify the mechanism of prolonged polycythemia in chronic hypoxia. The numbers of erythroid colony-forming units (CFU-E) in the spleen remarkably increased along with elevated serum EPO levels indicating the activation of erythropoiesis during the first 7 days of hypoxia. After 14 days of hypoxia, the numbers of CFU-E returned to normoxic levels, whereas polycythemia persisted for >140 days. Flow cytometry revealed a prolonged increase in the numbers of TER119-positive cells (erythroid cells derived from pro-erythroblasts through mature erythrocyte stages), especially the TER119 (high) CD71 (high) population, in bone marrow. The numbers of annexin-V-positive cells among the TER119-positive cells particularly declined under chronic hypoxia, suggesting that the numbers of apoptotic cells decrease during erythroid cell maturation. Furthermore, RT-PCR analysis showed that the RNA expression of BMP-4 and stem cell factor that reduces apoptotic changes during erythroid cell proliferation and maturation was increased in bone marrow under hypoxia. These findings indicated that decreased apoptosis of erythroid cells during erythropoiesis contributes to polycythemia in mice during chronic exposure to long-term hypoxia.

Increased Erythropoiesis in Mice Injected With Submicrogram Quantities of Pseudouridine-containing mRNA Encoding Erythropoietin

Advances in the optimization of in vitro-transcribed mRNA are bringing mRNA-mediated therapy closer to reality. In cultured cells, we recently achieved high levels of translation with high-performance liquid chromatography (HPLC)-purified, in vitro-transcribed mRNAs containing the modified nucleoside pseudouridine. Importantly, pseudouridine rendered the mRNA non-immunogenic. Here, using erythropoietin (EPO)-encoding mRNA complexed with TransIT-mRNA, we evaluated this new generation of mRNA in vivo. A single injection of 100 ng (0.005 mg/kg) mRNA elevated serum EPO levels in mice significantly by 6 hours and levels were maintained for 4 days. In comparison, mRNA containing uridine produced 10–100-fold lower levels of EPO lasting only 1 day. EPO translated from pseudouridine-mRNA was functional and caused a significant increase of both reticulocyte counts and hematocrits. As little as 10 ng mRNA doubled reticulocyte numbers. Weekly injection of 100 ng of EPO mRNA was sufficient to increase the hematocrit from 43 to 57%, which was maintained with continued treatment. Even when a large amount of pseudouridine-mRNA was injected, no inflammatory cytokines were detectable in plasma. Using macaques, we could also detect significantly-increased serum EPO levels following intraperitoneal injection of rhesus EPO mRNA. These results demonstrate that HPLC-purified, pseudouridine-containing mRNAs encoding therapeutic proteins have great potential for clinical applications.

Impact of increased erythropoietin receptor expression and elevated serum erythropoietin levels on clinicopathological features and prognosis in renal cell carcinoma

Erythropoietin (EPO) expression and EPO receptor (EpoR) expression have been demonstrated in various malignant tumors. EPO-EpoR signaling can activate several downstream signal transduction pathways that enhance tumor aggressiveness. The present study was undertaken to evaluate the impact of overexpression of EpoR and elevated serum EPO (sEPO) levels on the clinicopathological features and prognosis of patients with renal cell carcinoma (RCC). EpoR expression was evaluated immunohistochemically in 56 patients. Tumors with a staining intensity greater than that of surrounding proximal tubules were defined as tumors with high EpoR expression. The association between EpoR expression levels and various clinicopathological factors was analyzed. sEPO levels were determined in 138 patients and its correlation to clinicopathological factors was also analyzed, and EpoR expression was determined in surgical specimens removed from 47 of those 138 patients. Patients with high EpoR expression and patients with sEPO elevation had clinicopathological features less favorable than those of other patients. Tumors demonstrating high EpoR expression had a significantly higher number of Ki-67-positive cells compared to those with low EpoR expression. Tumor assemblies in microvessels demonstrated high EpoR expression. Patients whose tumors demonstrated high EpoR expression and those with sEPO elevation had a significantly lower survival rate compared to other patients, and patients with both high EpoR expression and sEPO elevation had an extremely poor prognosis. Microvascular invasion was an independent factor associated with sEPO elevation, suggesting that EPO-EpoR signaling might be important in RCC metastasis. EPO-EpoR signaling may be involved in tumor growth and progression in RCC and the combination of EpoR expression and sEPO levels may effectively predict clinical outcome.

Polycythemia due to obstructive sleep apnea in a patient on hemodialysis

Both anemia and sleep disordered breathing are common in patients with dialysis-dependent stage 5 chronic kidney disease. Erythrocytosis resulting from obstructive sleep apnea (OSA) is rare in the general population and has never been described in the hemodialysis population. We present a case of asymptomatic isolated erythrocytosis and elevated serum erythropoietin level in an otherwise well and previously erythropoietin-dependent chronic hemodialysis patient with chronic kidney disease secondary to ischemic nephropathy. There was no history or symptoms of cardio-pulmonary or hepatic diseases nor any relevant family history. Screening work-up for malignancies was negative. The clinical history was highly suggestive of OSA and severe OSA (respiratory disturbance index of 59) was confirmed by polysomnographic studies. Successful treatment of the OSA with continuous positive airway pressure resulted in permanent stabilization of the hemoglobin to levels below 13 g/dL without the need for repeated phlebotomies and in dramatic lowering of serum erythropoietin levels. To our knowledge, this is the first case of OSA mediated erythrocytosis in a dialysis patient documented in the literature.

Abstract 2362: High Serum Erythropoietin Level is Associated with Poor Prognosis in Heart Failure Patients with Systolic Dysfunction but not with Preserved Systolic Function

Introduction: It is known that serum levels of erythropoietin (EPO) are elevated in patients with chronic heart failure (CHF) and correlate with the severity of CHF. Serum EPO levels have been examined in stable CHF patients with LV systolic dysfunction (LVSDF) but not in patients with preserved LV ejection fraction (PLVEF). Moreover, the data about EPO are also lacking in acute decompensated HF (ADHF) patients. Hypothesis: Serum EPO levels may be different between patients with LVSDF and with PLVEF, and between patients in an acute decompensated state and in a stable, compensated state. Methods: We studied 52 patients who were admitted to our hospital with ADHF (NYHA functional class of III or IV). There were 22 females, and mean age was 73 years. They were divided into 2 groups: LVSDF (LV ejection fraction (EF) &lt; 45%, n = 37) and PLVEF (LVEF ≥ 45%, n = 15). Serum EPO, hemoglobin (Hb) and plasma brain natriuretic peptide (BNP) levels were measured on admission and after treatment. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease Study equation. Results: On admission, serum EPO levels were higher in the LVSDF than in the PLVEF groups (84 ± 12 vs. 55 ± 9 mU/ml, p &lt; 0.05). After treatment, NYHA functional classes equally improved to I or II, and serum EPO and plasma BNP levels decreased in both groups (LVSDF: 31 ± 5 vs. 84 ± 12 mU/ml, p &lt; 0.05; 526 ± 82 vs. 1134 ± 163 pg/ml, p &lt; 0.05; PLVEF: 24 ± 4 vs. 55 ± 9 mU/ml, p &lt; 0.05; 240 ± 53 vs. 523 ± 87 pg/ml, p &lt; 0.05). The Hb levels and eGFR were not different between the groups on admission. When plasma BNP levels were matched between the 2 groups, the same tendency was observed in the levels of EPO. The higher EPO levels (&gt; 50 mU/ml) in ADHF were associated with higher incidence of cardiac death or HF hospitalizations (log-rank test, p &lt; 0.05) only in the LVSDF group. Conclusions: Serum EPO levels were higher in patients with LVSDF than in those with PLVEF in ADHF. Elevated serum EPO levels were associated with a poor prognosis in the LVSDF group, but not in the PLVEF group. Serum EPO levels may be useful prognostic value only in HF patients with LVSDF.

Postmortem serum erythropoietin levels in establishing the cause of death and survival time at medicolegal autopsy

Circulating erythropoietin (EPO) is mainly produced in the kidneys, depending on blood oxygen level. The present study investigated the postmortem serum EPO levels with regard to the cause of death and survival time. Serial medicolegal autopsy cases of postmortem time within 48 h (n = 536) were examined. Serum EPO levels were within the clinical reference range in most cases. Uremic patients with medical administration of an EPO agent (n = 11) showed a markedly high level (140-4,850 mU/ml; median, 1,798 mU/ml). Otherwise, an elevation in serum EPO level (>30 mU/ml) was mainly seen in protracted deaths due to blunt injury and fire fatality, depending on the survival time (r = 0.69, p < 0.0001, and r = 0.45, p < 0.0001, respectively), and in subacute deaths from gastrointestinal bleeding and infectious diseases. However, mildly to moderately elevated serum EPO levels were sporadically found in acute deaths due to mechanical asphyxiation, fire fatality, and acute ischemic heart disease, and in fatal hypothermia cases, especially for elderly subjects. Protracted deaths due to mechanical asphyxiation and ischemic heart disease did not show any survival time-dependent increase in serum EPO level (p > 0.05). EPO was immunohistochemically detected in the tubular epithelia and interstitial cells, showing no evident difference among the causes of death, independent of survival time or serum level. These findings suggest that serum EPO can be used as a marker for investigating anemia and/or hypoxia as a consequence of fatal insult in subacute or prolonged deaths, or a predisposition to traumatic deaths or fatal heart attacks in acute deaths.

Homeostatic erythropoiesis by the transcription factor IRF2 through attenuation of type I interferon signaling

Erythrocyte production is tightly regulated by cytokines, particularly erythropoietin (EPO), which affects expansion and viability of erythroid lineage cells via induction of several factors, including Bcl2-like 1 (Bcl-XL). Because type I interferon (IFN) is known to inhibit erythropoiesis, we studied mice deficient in the gene for interferon regulatory factor 2 (IRF2), which functions as a negative regulator of type I IFN signaling, in the context of erythropoiesis regulation. We performed hematologic analyses and detected normocytic anemia in Irf2-deficient mice. Assessment of the maturation of erythroid progenitors in Irf2-deficient bone marrow by flow cytometry revealed a decreased number of late erythroblasts accompanied by an increased number of early erythroid progenitors. Irf2-deficient mice manifested elevated serum EPO levels, decreased Bcl-XL expression levels and enhanced apoptosis of erythroblasts, which may account for the decreased number of late erythroblasts. We further assessed the role of IRF2 in the regulation of type I IFN signaling during erythropoiesis, and found that additional homozygous mutation of IFNAR1, a subunit of type I IFN receptor complex, led to rescue of the defect of erythropoiesis in Irf2-deficient mice. Impaired erythropoiesis in Irf2-deficient mice results from excessive type I IFN signaling, which inhibits Bcl-XL expression in erythroid lineage cells. Our present study provides a mechanistic understanding of the potential cross-talk between type I IFN and EPO signaling pathways during erythropoiesis and may offer therapeutic insights into anemia.

Elevated serum erythropoietin levels in patients with Budd‐Chiari syndrome secondary to polycythemia vera: clinical implications for the role of JAK2 mutation analysis

It is widely accepted that an increased serum endogenous erythropoietin (Epo) level in a patient presenting with an elevated red cell mass makes a diagnosis of clonal polycythemia vera (PV) extremely unlikely. However, until the recent description of the constitutively activating V617F point mutation of the Janus 2 tyrosine kinase (JAK2)--a high-frequency molecular marker that is extremely specific for clonal chronic myeloproliferative disorders--distinction of PV from secondary erythrocytosis or other conditions has often been difficult. The purpose of this study was to use JAK2 V617F analysis to re-evaluate the validity of elevated Epo levels as a PV-exclusion criterion in patients with hepatic vein thrombosis [Budd-Chiari syndrome (BCS)]. We reviewed clinical data from 30 patients at our institution who presented with erythrocytosis and BCS. We isolated myeloid cells from fresh or archival bone marrow samples from four patients with BCS and an elevated serum Epo level, and analyzed them for the presence of the JAK2 V617F mutation. All four samples were positive for JAK2 V617F, confirming the presence of a clonal hematopoietic disorder consistent with PV. In the presence of BCS, elevated serum Epo levels do not exclude the diagnosis of PV.

Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma

The von Hippel-Lindau (VHL) tumor suppressor gene targets hypoxia-inducible transcription factors (HIFs) for proteasomal degradation. Erythrocytosis due to inappropriate production of erythropoietin (EPO), one of the HIF target genes, is a classic albeit rare finding in patients with renal cancer. We report the clinical to molecular analysis in a patient in whom a thrombotic myocardial infarction was the first manifestation of a clear cell renal carcinoma associated with an elevated serum EPO level (109 U/L) and erythrocytosis (hemoglobin 200 g/L [20 g/dL]). The tumor strongly expressed EPO messenger RNA and the 2 regulatory subunits HIF-1alpha and HIF-2alpha. Sequence analysis of tumor tissue identified a point mutation of the VHL gene (nucleotide 701 T > C) with a predicted amino acid exchange (Leu163Pro). This structural change, although located at distance to the HIF-binding region, was found to inhibit binding of HIF-1alpha to VHL, thus leading to accumulation of HIF, which drives EPO production.

Phase II Study of Subcutaneous Erythropoietin for Treatment of Myelodysplastic Syndromes (FAB Type I and II): A Trial of the Phase l/ll Study Group of the Association for Medical Oncology of the German Cancer Society

<i>Background</i>: Anemia in patients with myelodysplastic syndromes (MDS) is usually put down to ineffective erythropoiesis, although the contributory role of other mechanisms has not been sufficiently understood until now. Evidence has been found that in some cases of MDS erythropoietin (EPO) is able to restore anemia to a certain extent. Especially in cases of MDS with a relatively good prognosis, such as refractory anemia (RA) and refractory anemia with ring sideroblasts (RARS), a benefit may be expected for patients treated with EPO since blood transfusion and its associated risks could be spared or at least markedly reduced. <i>Patients and Methods</i>: In a phase II study a total of 26 patients was recruited (female 15, male 11; median age 72 years). 15 patients with RA and 11 patients with RARS were initially treated with 5,000 IU EPO s. c. daily for 4 weeks. In case of response, treatment was continued up to 24 weeks; in case of nonresponse, the EPO dose was augmented to 10,000 IU s.c. for a further 4 weeks. If there was still no response, treatment was stopped, otherwise it was continued up to 24 weeks. Treatment response was defined as an increase of hemoglobin by at least 2 g/dl with unchanged transfusion rate or a major reduction of transfusion rate by at least 30%. <i>Results</i>: 26 patients were evaluable. 5 patients – 2 with RA, 3 with RARS – responded with a major reduction of transfusion rate ( > 30%) to therapy with 10,000 IU EPO daily. 5 patients showed a minor response ( < 30%). No patient showed a significant increase of Hb ( > 2 g/dl). In 2 patients treatment had to be stopped. Two of the responding patients showed elevated endogenous serum EPO levels ( > 200 U/l) prior to therapy. <i>Conclusion</i>: EPO shows an effective reduction of transfusion rates in MDS patients with RA or RARS in only 25%. Thus it cannot be generally recommended. Response to treatment may occur even if initial endogenous EPO levels are markedly increased.

Serum erythropoietin levels after renal transplantation.

We measured serum erythropoietin levels serially in 31 renal-transplant recipients treated with cyclosporine, using the recently developed recombinant human erythropoietin-based radioimmunoassay. The mean (+/- SEM) serum erythropoietin concentration in these patients before transplantation (14 +/- 2 U per liter) was similar to that in normal subjects who did not have anemia. A transient postoperative 9-fold increase (range, 0- to 74-fold) in the serum erythropoietin levels was followed by a smaller (3-fold) and sustained (28 +/- 3 days) second elevation. The initial increase occurred in the absence of graft function and was not accompanied by an erythropoietic response, whereas the second increase was associated with graft recovery and the complete resolution of the anemia. Serum erythropoietin levels returned to normal as the hematocrit rose above 0.32. Thereafter, the hematocrit continued to rise toward normal, while the serum erythropoietin levels remained normal. The patients in whom erythrocytosis or iron-deficiency anemia developed had persistently elevated serum erythropoietin levels. We conclude that in patients who have undergone renal transplantation, slight increases in endogenous erythropoietin levels induce erythropoiesis to the same extent as do large doses of exogenous erythropoietin in patients with uremia. Moreover, once initiated, erythropoiesis in renal-transplant recipients may be sustained by normal serum erythropoietin levels. These results suggest that the restoration of renal function improves the erythropoietic response to erythropoietin.

Infants and children with haematological disease

Infants and children with haematological disease