Erythropoietin Response In Patients Research Articles

The Role of Zinc and Copper in Anemia and Erythropoietin Responsiveness in Patients on Hemodialysis and Peritoneal Dialysis

Introduction: Imbalance in copper (Cu) and zinc (Zn) homeostasis is a frequent finding in patients undergoing dialysis. These patients have higher serum Cu and lower serum Zn levels compared to controls. This study is designed to investigate the relationship between blood Cu and Zn levels and Cu/Zn ratio and, ESA (erythropoietin stimulating agent) dosage, erythropoietin responsiveness and anemia in dialysis patients. Methods: Clinical and demographic data for 151 participants (men=79) with a median dialysis vintage of 69.7 months [101 on Hemodialysis (HD), 50 on Peritoneal Dialysis (PD)] and mean age of 56.25±15.6 years was collected in November 2022. Zn and Cu levels were measured with atomic absorption. Erythropoietin responsiveness was evaluated by the erythropoietin resistance index (ERI) and ESA dosing. Results: In HD patients, mean serum Zn and Cu levels were 61.33 ± 15.77 μg/dL and 95.1 ± 21.1 µg/dL, respectively, with a Cu/Zn ratio of 1.58 ± 0.69. In PD patients, mean serum Zn and Cu levels were 54.8 ± 10.3 µg/dL and 97 ± 20.2 µg/dL, respectively, with a Cu/Zn ratio of 1.72 ± 0.55. In Spearman analyses serum Cu was negatively correlated with hemoglobin (p=0.018), serum iron (p=0.03), transferrin saturation (p=0.019), and iron supplementation (p <0.01) in the HD patient group. Serum Cu was found to be positively correlated with erythropoietin (EPO) dosage (p=0.03), ERI (p=0.04), high sensitive C reactive protein (hsCRP) (p=0.01), and Kt/V (p=0.033). Cu/Zn ratio was positively correlated with EPO dosage (p=0.043), ERI (p=0.051) and hsCRP (p=0.015). Conversely, it was negatively correlated with iron supplementation (p=0.014) and serum albumin levels (p=0.049). Serum Zn levels was solely correlated with albumin level (p=0.039). In PD, patient’s serum Cu level was correlated positively with hsCRP (p=0.036); serum Zn levels correlated positively (p=0.01), and Cu/Zn ratio was correlated negatively with albumin (p=0.042). Conclusion: This study has shown a possible association between both serum Cu and Cu/Zn ratio, ESA dosage and hsCRP in HD patients.

Serum hepcidin levels and erythropoietin resistance in hemodialysis patients

Introduction Erythropoietin (EPO) resistance is an important cause of anemia in patients with chronic kidney disease. Enhancement of erythropoiesis by EPO requires intact EPO signaling and effective mobilization of iron stores. Enhanced synthesis of hepcidin leads to reduction of iron absorption in the small intestine and sequestering of iron in macrophages. Hepcidin may contribute to EPO resistance through a direct inhibitory effect on erythroid progenitor proliferation and survival. Objective To assess serum hepcidin levels in patients undergoing hemodialysis (HD) treatment and to distinguish its analogous association with anemia parameters and EPO resistance. Patients and methods A cross-sectional study was carried out among HD patients at Nephrology Unit of the Zagazig University Hospital from 2017 to 2018. The study included 90 participants, meeting our inclusion criteria, who had end stage renal disease (ESRD) and were on regular HD three times weekly. All patients were subjected to full history taking and clinical and laboratory assessment. It included routine investigations, with complete blood picture, calcium, phosphorus, parathyroid hormone (PTH), lipid profile, iron panel, and c reactive peptide (CRP). Specific investigations included the EPO resistance index and serum hepcidin measurement. Results Hepcidin is positively related to EPO resistance index. EPO resistance index as well as ferritin were significant determinants of hepcidin in HD patients. Conclusion Hepcidin is associated with anemia, iron status, and microinflammation in HD patients. If used as a diagnostic tool, it might improve iron therapy during periods of reticuloendothelial blockage of iron transport. This is important to avoid iron overload and to improve EPO response in patients with ESRD.

Erythropoietin Response in Patients with Anaemia of Chronic Disorders

Erythropoietin Response in Patients with Anaemia of Chronic Disorders

Analysis of the correlation between serum resistin and the variability of erythropoietin responsiveness in patients with chronic kidney disease.

Chronic kidney disease (CKD) is commonly accompanied by inflammation and anemia; however, the pathogenesis of CKD is unclear. Expression of resistin, a cysteine-rich secretory plasma protein, is correlated with the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and lipoprotein-associated phospholipase A2, indicating that resistin may be involved in inflammatory events. In addition, inflammation inhibits the activity of erythropoietin (EPO) and, thus, erythropoiesis. The aim of the present study was to analyze the correlation between serum resistin and the variability of EPO responsiveness in CKD patients. The levels of serum creatinine (SCr), C-reactive protein (CRP), total cholesterol, triglycerides, IL-6 and serum resistin were measured in the samples obtained from 138 CKD patients and healthy control subjects. The levels of serum resistin in the CKD groups with and without hemodialysis were significantly higher than those observed in the normal control group (P<0.01) and the levels of serum resistin in the hemodialysis CKD group were higher than those observed in the CKD group without dialysis (P<0.01). The levels of serum resistin in patients in the randomly selected CKD group (with hemodialysis) were positively correlated with the duration of dialysis and the levels of SCr and CRP (P<0.05), however, were negatively correlated with the estimated glomerular filtration rate. The EPO resistance index (ERI) was identified to be associated with body mass index and the levels of CRP and resistin; furthermore, EPO reactivity was correlated with the level of resistin and ERI. The levels of serum resistin were correlated with the variability in EPO responsiveness that was observed in the CKD patients. Therefore, the measurement of serum resistin may aid with understanding the mechanisms, clinical diagnosis and treatment of CKD.

Increased hepcidin-25 and Erythropoietin Responsiveness in Patients With cardio–renal Anemia Syndrome

Hepcidin is a key regulator controlling iron intestinal absorption and distribution through the body. The article by van der Putten et al. examined the association between hepcidin-25 and erythropoietin responsiveness and inflammation in erythropoietin-naive, iron-replete patients with chronic heart failure and chronic kidney disease. A cross-sectional observation revealed that serum hepcidin-25 was elevated almost twofold when compared with levels in healthy subjects. Hepcidin-25 was inversely correlated with hemoglobin (r(2) = 0.18; p < 0.02), and positively with ferritin (r(2) = 0.51; p < 0.01) and transferrin saturation (r(2) = 0.14; p < 0.03), while it did not correlate with levels of IL-6 and highly sensitive C-reactive protein. They found that 2-week erythropoietin therapy (50 IU/kg/week) significantly decreased hepcidin-25 levels. The magnitude of the decrease in hepcidin-25 levels correlated with the increase in reticulocytes (r(2) = 0.23; p < 0.03) and soluble transferrin receptor (r(2) = 0.23; p = 0.03), but not with inflammatory markers. A decline in hepcidin-25 correlated with the increment of hemoglobin after 6 months (r(2) = 0.49; p < 0.01). The findings convincingly suggest that hepcidin-25 may be useful in predicting erythropoietin responsiveness in stable chronic heart failure patients. However, further studies will be needed to establish clinically available methods to reliably measure hepcidin-25 level.

Serum erythropoietin concentrations and responses to anaemia in patients with or without chronic kidney disease

Renal anaemia is caused by a relative erythropoietin (EPO) deficiency. Due to difficult interpretation of serum EPO concentrations adapted to anaemia and renal function, the diagnostic value of measuring serum EPO concentrations is limited. We retrospectively analysed the relationship between haemoglobin and serum EPO concentrations routinely measured in in- and out-patients of our university hospital from 2001-04. Patients under EPO substitution or those with acute renal failure, polycystic kidney disease, renal carcinoma or polycythaemia due to pulmonary disease were excluded. The study population (n = 500) was then stratified according to the presence or absence of chronic kidney disease (CKD) and to the stage if CKD was present. EPO concentrations were expressed in percentiles corrected for the severity of anaemia and based on the EPO response in patients without CKD. In patients without CKD (n = 167) there was a strong parametric correlation between severity of anaemia and increase in EPO (r = -0.81). Linear regression of the log-transformed EPO values revealed the equation log EPO (mIU/ml) = -0.135 x Hb (g/dl) + 2.821 (r(2) = 0.65). With increasing stages of CKD the correlation between haemoglobin and EPO concentrations was gradually attenuated and was completely lost in CKD stage four and five. In anaemic patients with Hb < 11 g/dl, relative EPO deficiency defined as EPO concentrations below the 25th percentile was present in 38%, 67%, 93% and 100% of the patients with CKD stages 1-5, respectively. Expression of EPO concentrations in percentiles improves the diagnostic value of measuring EPO concentrations for diagnosing relative EPO deficiency and renal anaemia.

BLOOD LOSS AND THE NEED FOR TRANSFUSION IN PATIENTS WHO UNDERGO PARTIAL OR RADICAL NEPHRECTOMY FOR RENAL CELL CARCINOMA

We assessed blood loss and subsequent transfusion associated with nephrectomy performed for suspected renal cell carcinoma to establish guidelines for preoperative autologous blood donation and identify a subgroup of patients that may benefit from erythropoietin administration. We retrospectively reviewed the charts of 211 patients who underwent partial (73%) or radical (23%) nephrectomy for presumed renal cell carcinoma at our institution between 1990 and 1999. Patients were divided into groups 1-44.5% treated with radical nephrectomy for localized disease, 2-21.3% radical nephrectomy for metastatic lesions invading the renal vasculature or inferior vena cava, 3-8% radical nephrectomy for metastatic disease with locally extensive lesions and 4-26.5% partial nephrectomy for localized lesions. Patient charts were evaluated for preoperative and postoperative hematocrit, estimated blood loss, transfusions received, surgical complications and underlying disease. Median estimated blood loss was 200, 400, 250 and 555 cc in groups 1 to 4, respectively. However, patients in groups 2 and 3 had a substantially greater range of blood loss than those in groups 1 and 4, respectively. The incidence of those with a blood loss of greater than 1 l. was 7%, 36%, 24% and 11% in groups 1, to 4, respectively. The incidence of those requiring transfusion was significantly lower in group 1 than in groups 2 to 4 (18% versus 44%, 24% and 30%, respectively, p <0.009). Mean transfusion requirement plus or minus standard deviation was significantly greater in groups 2 and 3 than in 1 and 4 (2.3 +/- 1.08, 5.5 +/- 4.4, 11.3 +/- 9.6 and 2.3 +/- 1.7 units, respectively, p <0.05). No significant difference was noted in the change in hematocrit as a result of surgery in the 4 groups (p >0.05). Similarly underlying disease and operative complications did not have a significant effect on blood loss or transfusion (p >0. 05). Radical or partial nephrectomy for localized renal cell carcinoma leads to consistent and well tolerated operative blood loss that rarely results in the need for substantial transfusion. In contrast, nephrectomy for advanced disease may cause a risk of greater blood loss and subsequent need for the transfusion of multiple units of blood. While preoperative autologous blood donation may have limited value in this regard due to the high cost and number of units needed, preoperative erythropoietin administration may be a viable option. Prospective randomized studies are currently planned.

Response and prediction of response to recombinant human erythropoietin in patients with solid tumors and platinum-associated anemia

Objective. Anemia is commonly observed in tumor patients and may be worsened by the concomitant administration of chemotherapy with platinum. Recombinant human erythropoietin (rhEPO) is able to improve the chemotherapy-associated anemia and the quality of life in patients with solid tumors. The most effective dose, route, and frequency of administration of rhEPO in anemic cancer patients has not yet been determined. The purpose of this review is to describe the results obtained up to now concerning the response and prediction of response to rhEPO in anemic patients with solid tumors undergoing platinum-based chemotherapy. In particular, the renal function conditions in this patient group were examined. Data sources. The literature was reviewed through a MEDLINE search covering 1987 to 1997. Relevant articles were additionally obtained by the systematic examination of article references. We searched the following terms: rhEPO, tumor, anemia, cisplatin, carboplatin, and renal failure. Study Selection. The current literature was reviewed with regard to both the pathophysiology of platinum-induced anemia and the clinical use, indications, and dosage of rhEPO in anemic tumor patients undergoing platinum therapy. Particular attention was directed to the prediction criteria of this drug. Conclusions. The rhEPO response rates in patients with solid tumors and platinum-associated anemia vary widely in the current literature and range from 36% to 82%. Unfortunately, no strong predictor of response can be recommended at the present time. Clinical studies support findings concerning a reduction in renal function parameters and a blunted erythropoietin response in patients with platinum-induced anemia. It is possible that a baseline serum erythropoietin concentration in conjunction with the serum creatinine concentration or the creatinine clearance value can serve as a prognostic indicator for rhEPO therapy response in this patient group.

Blunted serum erythropoietin response to anemia in patients polytransfused for beta-thalassemia major.

To investigate the response of erythropoietin (EPO) to anemia in patients polytransfused for beta-thalassemia major. We measured the serum EPO levels and the concurrent hemoglobin (Hb) concentrations in 40 patients polytransfused for beta-thalassemia major, in 18 patients with iron deficiency anemia (IDA), and 32 healthy subjects. Serum EPO levels were assayed by an enzyme immunoassay. In both groups with beta-thalassemia major and IDA, serum EPO levels were significantly elevated (114 +/- 71 and 239 +/- 217 mU/mL, respectively). There was a significant inverse correlation between log EPO values and Hb concentrations in patients with beta-thalassemia major (r = 0.61; p < 0.01) and IDA (r = 0.81; p < 0.01). In a semilogarithmic plot, the slope of the regression line obtained in patients with beta-thalassemia major was significantly lower than that of IDA (p < 0.01), suggesting a blunted EPO response to anemia in patients polytransfused for beta-thalassemia major. The elevation of serum EPO in patients with beta-thalassemia major was poorly related to clinical variables except serum ferritin. We conclude that a significant inverse relationship between serum EPO levels and Hb concentration exists in patients with beta-thalassemia major. However, this EPO response in patients with anemia caused by beta-thalassemia major may be blunted when compared to patients with IDA.

Control of post-transplant erythrocytosis by enalapril.

To assess the erythropoietin response in patients with erythrocytosis after renal transplantation who were treated with enalapril. Fourteen patients with stable renal transplants (creatinine clearance, 74.4 +/- 24.6 mL/min) and a packed cell volume of 51% or more over six months and who had no other cause for their erythrocytosis. Patients were treated with enalapril for six months. Serum erythropoietin levels, creatinine clearance and packed cell volume were measured before and during the study; patients were reviewed each month. All patients had erythropoietin levels inappropriate for their packed cell volume. After six months' therapy with enalapril their mean erythropoietin concentration of 21.3 +/- 5.0 U/L fell to 7.4 +/- 1.3 U/L (P < 0.02) although the concentration increased in two patients. The mean packed cell volume fell from 52.7% +/- 0.5% to 44.4% +/- 1.0% (P < 0.0001). There was no change in renal function. Low-dose enalapril controls post-transplant erythrocytosis, at least in part, by lowering serum erythropoietin levels.

The secretory erythropoietin response in patients with multiple myeloma and Waldenstrom's macroglobulinaemia

The secretory erythropoietin response in patients with multiple myeloma and Waldenstrom's macroglobulinaemia

Decreased Erythropoietin Response in Patients with the Anemia of Cancer

Patients with solid tumors are often anemic even before they undergo cytotoxic therapy. Since the cause of the anemia of cancer is unknown, we examined the possible role of erythropoietin. Using a sensitive radioimmunoassay, we determined serum immunoreactive erythropoietin levels in 81 anemic patients with solid tumors. For any given degree of anemia, the serum concentration of immunoreactive erythropoietin was lower in this group of patients than in a group of control patients with iron-deficiency anemia (P = 0.0001). Furthermore, the expected inverse linear relation between serum levels of immunoreactive erythropoietin and of hemoglobin was absent in the group with cancer. The erythropoietin response was further decreased in patients receiving chemotherapy; it was not influenced by the presence or absence of cisplatin in the treatment regimen. The inability of the patients with cancer to produce erythropoietin was not absolute; if they had hypoxemia, adequate erythropoietin production was restored. We conclude that erythropoietin levels are inappropriately low in anemia associated with cancer, and that erythropoietin deficiency may contribute to the development of this form of anemia. Treatment of the anemia of cancer with erythropoietin may be of value.

The secretory erythropoietin response in patients with multiple myeloma and Waldenstrom's macroglobulinaemia

Immunoreactive levels of serum erythropoietin (EPO) have been measured in 95 patients with multiple myeloma (MM) and 12 patients with Waldenström's macroglobulinaemia (MW). Of the MM patients 23% were uraemic (mostly light and moderate renal failure) and 61.7% were anaemic. In the anaemic nonuraemic MM patients the mean serum EPO titre was 106.8 +/- 30.4 mU/ml which, when related to the extent of anaemia, was found to be appropriately elevated for the degree of anaemia (the mean haemoglobin (B-HGB) concentration was 6.66 +/- 1.31 mmol/l). The mean serum EPO concentration in uraemic and anaemic MM patients was 39.2 +/- 9.2 mU/ml, which was markedly lower than serum EPO levels in the non-uraemic MM patients, but still higher than in nonanaemic control subjects (22.5 +/- 8.5 mU/ml). The mean B-HGB concentration in uraemic MM patients was 6.04 mmol/l. In the anaemic MM patients with severe renal failure (S-creatinine levels greater than 400 mumol/l) the compensatory secretion of EPO was inadequate in relation to the degree of anaemia. The data indicate that unless the hypoproliferative anaemia of MM is accompanied by considerable renal failure the anaemia does not appear to be associated with a deficient biogenesis of EPO. Likewise the anaemia found in patients with MW also seems, generally, to elicit an appropriate increase in EPO secretion. Reasonably clinically stable MM patients with anaemia and uraemia may be candidates for replacement therapy with recombinant human erythropoietin (rhEPO).