Erythropoiesis after Therapy with Recombinant Human Erythropoietin: A Dose-Response Study in Anemic Cancer Surgery Patients

Background and Objectives: Preoperative treatment with 600 U/kg of recombinant human erythropoietin (r-HuEPO) effectively increases erythropoiesis in cancer patients. The aim of this study was to evaluate the erythropoietic response after different doses of r-HuEPO in order to find the minimum effective dose. Materials and Methods: Twenty anemic sideropenic patients (hemoglobin ≤ 110 g/l; serum iron <600 μg/l) with cancer of the gastrointestinal tract were randomly allocated to two groups: the first (n = 10) received 400 U/kg of r-Hu EPO divided in 4 doses (100 U/kg each, every 4 days); the second (n = 10) received 200 U/kg of r-HuEPO (50 U/kg each, every 4 days). Both groups were given intravenous iron gluconate (125 mg) every day for 15 days. Results: After treatment, the serum iron level significantly rose in both groups. The production of new red blood cells was 176.3±90.8 ml in the 200 U/kg group and 268.4±79.4 ml in the 400 U/kg group (p = 0.036). The increase of hemoglobin was significantly higher in the 400 U/kg group (22.3±2.0 g/l) than in the 200 U/kg group (14.1±2.7 g/l) (p = 0.017). Conclusion: The r-HuEPO dose of 400 U/kg appears significantly more effective than the 200 U/kg to stimulate erythropoiesis in anemic sideropenic cancer patients.     

Plasma Endothelin Levels and Blood Pressure in Hemodialysis and in Capd Patients. Effect of Subcutaneous Erythropoietin Replacement Therapy

We investigated plasma endothelin (ET) concentration and blood pressure in 44 patients with end stage renal failure chronically treated with either hemodialysis (n = 24) or continuous ambulatory peritoneal dialysis (CAPD) (n = 20). Half of the subjects were on chronic erythropoietin (r-HuEPO) replacement therapy (30-60 U/kg) subcutaneously, 3 times weekly. The mean plasma ET level of the whole group was about five fold higher than the normal range. Plasma ET concentration and mean blood pressure were higher in hemodialysis than in CAPD patients (33.3 ± 2.1 vs 24.8 ± 1.2 pg/ml, p < 0.01, and 101 ± 2.4 vs 91 ± 3 mmHg, p < 0.025). There was a significant correlation between plasma ET levels and systolic blood pressures in both groups (r = 0.45, p < 0.05). Patients (hemodialysis and CAPD) receiving subcutaneous r-HuEPO had higher mean blood pressure (99 f 3 vs 85 Ifi 4 mmHg, p < 0.01), while their plasma ET levels were similar to untreated patients independent of the dialysis mode. However, a statistically significant correlation between plasma ET and systolic blood pressure was present only in the r-HuEPO treated group (r = 0.46, p < 0.05 vs r = 0.29, N.S., for the untreated group). These results show that plasma ET levels are markedly increased on both dialysis mode, but the values are lower in CAPD patients. Plasma ET concentrations significantly correlated with systolic blood pressures in the whole group of patients, and also in those receiving r-HuEPO replacement therapy.     

Low dose erythropoietin in maintenance haemodialysis: improvement in quality of life and reduction in true cost of haemodialysis

Abstract Human recombinant erythropoietin (r-HuEPO) improves quality of life in patients on maintenance haemodialysis, but the haemoglobin (Hb) level necessary to achieve this improvement is unknown. In this study, quality of life, functional capacity and symptoms of 28 haemodialysis patients with an initial Hb of 67 ±2 (mean ± SEM) g/L were assessed after 0, 6 and 12 months of r-HuEPO, the dose of which was titrated to achieve a stable Hb of between 90 and 100 g/L. At six and 12 months Hb was 97 ± 2 and 93+2 g/L, and mean r-HuEPO dose between three and six, and between nine and 12 months was 88 ± 6 and 62 ± 9 U/kg/week intravenously respectively. There was a significant improvement in level of activity and satisfaction with various aspects of life, and a reduction in fatigue, weakness, dyspnoea, angina and restless legs. Patients were able to walk 50% further in six minutes. The improvement in quality of life and function was similar to that reported from other centres whose target Hb was between 100 and 120 g/L, and where the r-HuEPO dose was 75% higher than in this study. Costs of r-HuEPO therapy were assessed. The drug itself costs $A3681/yr/patient, to which was added the estimated cost of additional dialyses and medications, bringing the total to $A5177/yr/patient. There was, however, a reduction in both hospitalisation by 8.3 days/yr/patient and medical consultation by 3.9 hours/yr/patient. Five patients commenced full-time work, one took up full-time study aimed at finding work, three transferred to home haemodialysis and six fewer patients drew social security benefits. The net cost saving from using low dose r-HuEPO was more than $A1,000/yr/patient.     

Effects of parathyroidectomy on iron homeostasis and erythropoiesis in hemodialysis patients with severe hyperparathyroidism

AIMS: Secondary hyperparathyroidism (HPT) worsens anemia and may cause hyporesponsiveness to recombinant human erythropoietin therapy (r-HuEPO). To investigate the effect of parathyroidectomy (PTX) on iron homeostasis and erythropoiesis, we conducted a prospective study in chronic hemodialysis patients who underwent PTX. METHODS: Thirty-two patients were enrolled in this study. Based on the increases in hemoglobin level after PTX, patients were divided into responders and nonresponders. Iron homeostasis and erythropoiesis were assessed before and 1 and 3 months after PTX, hemoglobin and parathyroid hormone levels were monitored until 6 months after PTX. RESULTS: In the responders, increased hemoglobin levels were observed in 15 patients at 1 and 3 months after PTX (8.0 +/- 0.8 g/dl vs. 9.2 +/- 1.3 and 10.1 +/- 0.9 g/dl, p < 0.05). The nonresponders had higher pre-PTX hemoglobin levels than the responders (10.3 +/- 1.6 g/dl vs. 8.0 +/- 0.8 g/dl, p < 0.05). There was no further increase in hemoglobin at 6 months compared to 3 months after PTX in both groups. In neither group did PTX affect serum ferritin, transferrin saturation and serum erythropoietin level. Serum soluble transferrin receptor (sTfR) concentration was found to be higher in responders than in nonresponders (3.32 +/- 1.28 mg/l vs. 1.70 +/- 0.31 mg/l, p < 0.05). CONCLUSIONS: We conclude that PTX can improve anemia in hemodialysis patients with severe hyperparathyroidism and greater resistance to r-HuEPO therapy. The reversing of anemia does not involve altering iron mobilization. Pre-PTX hemoglobin and serum sTfR levels can predict the effect of PTX on correcting anemia.     

The effect of intravenous iron on the reticulocyte response to recombinant human erythropoietin

We studied the effect of intravenous (i.v.) adminisration of 200 mg of iron sucrose following an i.v. bolus injection of recombinant human erythropoietin (r-HuEPO; 300 U/kg body weight) in seven subjects and compared it with seven subjects treated with r-HuEPO alone. Reticulocytes, serum erythropoietin (EPO) and ferritin levels were studied at baseline and daily for the following 8 d. Use of i.v. iron abolished the marked reduction in serum ferritin observed with r-HuEPO administration. Although the total number of reticulocytes was not affected by i.v. iron administration, the reticulocyte Hb content and retHb (a measure in g/l of the Hb contained in all reticulocytes) were increased in the i.v. iron/r-HuEPO group compared with the group who received r-HuEPO alone. Therefore i.v. iron significantly potentiates the haemopoietic response to r-HuEPO in normal subjects.     

Multicenter study of darbepoetin alfa in the treatment of anemia secondary to chronic renal insufficiency on dialysis

This Spanish single-arm, multicenter, prospective clinical trial assessed the maintenance of hemoglobin concentrations (Hb) between 10-13 g/dL with unit doses of darbepoetin alfa and the safety of the treatment in dialysis patients. Eight-hundred twenty-six patients with chronic renal failure (CRF) (94% receiving haemodialysis and 6% receiving peritoneal dialysis) previously maintained on stable recombinant human erythropoietin (r-HuEPO) therapy with stable hemoglobin (Hb) concentrations (mean Hb concentration = 11.7 g/dL) were switched to darbepoetin alfa at a reduced dosing frequency for 24 weeks (a 20-week titration phase plus a 4-week treatment evaluation phase). Subjects receiving r-HuEPO two or three times weekly were switched to darbepoetin alfa once weekly, and those. who were receiving r-HuEPO once weekly were switched to darbepoetin alfa once every two weeks. The initial dose of darbepoetin alfa was determined from the r-HuEPO dose at inclusion into the study using a formula equating the peptide mass of the two molecules and rounding to the nearest available prefilled syringe dose. Overall, 86.8% of patients completed the 24-weeks of study. Changing the treatment from r-HuEPO to darbepoetin alfa and increasing the dose interval did not result in any clinically significant change in the Hb concentration. From base-line to the evaluation phase, the mean Hb fell 0.09 (95% CI, -0.2; -0.0) g/dl, with an increase of 0.19 (95% CI, 0.0;0.3) g/dL i.v. and a decrease of 0.22 (95% CI, -0.3; -0.1) g/dL s.c.). This maintenance of the mean Hb concentration was accompanied by a mean 9.8% reduction of the darbepoetin alfa dose (19.7% (95% CI, -24.9; -14.2) i.v. and 4.7% (95% CI, -8.5; -0.7) s.c. Treatment with darbepoetin alfa was well tolerated and no unexpected adverse events were reported. In conclusion, the replacement of previous r-HuEPO treatment by darbepoetin alfa in the therapy of anemia secondary to chronic renal failure in diaiyzed patients was effective, well tolerated, and decreased the frequency of dose administration compared with the previous r-HuEPO treatment. Darbepoetin alfa administered once weekly or once every two weeks maintained the baseline Hb levels whilst allowing dose reduction, which was higher in patients receiving i.v. darbepoetin alfa.     

Plasma and Blood Vessel Endothelin-1 Concentrations in Hypertensive Uremic Rats Treated with Erythropoietin

The present study was designed to evaluate whether changes in plasma and blood vessel endothelin-1 (ET-1) concentrations may play a role in the enhanced blood pressure response to recombinant human erythropoietin (r-HuEPO) replacement therapy in uremia. Renal failure was induced by 5/6 nephrectomy (Nx). Uremic rats received either r-HuEPO (100 u s.c. three times a week) or the vehicle for 5 weeks. They were compared to control rats receiving the vehicle. Systolic blood pressure (tail cuff method), hematocrit, serum creatinine, plasma and tissue ET-1 were measured at the end of the protocol. Immunoreactive ET-1 (ir-ET-1) was determined by radioimmunoassay of acid-extracts from the plasma, thoracic aorta and mesenteric arterial bed. Creatinine increased about three fold in Nx animals. Blood pressure in control rats was 120 ± 3 mmHg compared to 161 ± 6 mmHg in the Nx + vehicle group (p<0.01) and 199 ± 9 mmHg in the Nx + r-HuEPO group (p±0.01). Plasma ir-ET-1 levals were similar in the Nx + vehicle and Nx + r-HuEPO Groups (7.9 ± 1.0 and 7.8 ± 0.8 pg/ml). In contrast, thoracic aorta ir-Et-1 content was significantly higher in the Nx + r-HuEPO group than in the Nx + vehicle group (20.3 ± 2.9 vs 13.4 ± 1.9 pg, p<0.05). Simlar results were obtained in the mesenteric arterial bed. There were significant ocrrelations between blood pressure and ir-ET-1 content in the thoracic aorta (r=0.045, p<0.05) and in the mesenteric arterial bed (r=0.41, p<0.05). Vascular ET-1 content but not plasma levels are increased in uremic rats treated with r-HuEPO suggesting an increase in blood vessel ET-1 production which may play a role in the pathogenesis of r-HuEPO-induced hypertension     

Antioxidant Enzymes Show Adaptation to Oxidative Stress in Athletes and Increased Stress in Hemodialysis Patients

The aim of the study is to compare oxidative stress in hemodialysis patients in controls and in rowers. The patients are a model of decreased antioxidant capacity, and the athletes (rowers) are a model of the highest antioxidant capacity due to their chronic adaptation to demanding training. Thirty‐five subjects participated in the study, 9 patients with end‐stage renal disease treated by hemodialysis, 12 healthy young subjects from the normal population, and 14 rowers. The antioxidant enzymes catalase, superoxide dismutase, and glutathione peroxidase, as well as non‐transferrin‐bound iron as a promoter of free radical damage, were determined. Blood analysis was taken in dialysis patients in the morning, before the dialysis procedure. There was significantly higher activity of catalase in dialysis patients (catalase 4.26 ± 0.35 mkat/g Hb) compared to the controls (catalase 2.73 ± 0.38 mkat/g Hb) and rowers (catalase 1.71 ± 0.30 mkat/g Hb). Superoxide dismutase activity was significantly lower (10.42 ± 1.46 µkat/g Hb) than in the controls (11.94 ± 1.18 µkat/g Hb) and rowers (14.09 ± 0.92 µkat/g Hb). There was no significant differences between glutathione peroxidase activities in the three groups. Superoxide dismutase and Se were higher in rowers than in dialysis patients (P < 0.05). The concentrations of both non‐transferrin‐bound iron and ferritin were significantly higher in dialysis patients. Hemodialysis patients might have increased oxidative stress, which is characterized by significantly higher erythrocyte enzyme activity of catalase and lower activity of superoxide dismutase. Top rowers had increased superoxide dismutase and glutathione peroxidase, perhaps because of adaptation during training, which was not the case in dialysis patients and controls.     

Higher prevalence of anemia among pregnant immigrant women compared to pregnant ethnic Danish women

The aim of the study was to investigate whether the well-known high anemia prevalence in pregnant women from the eastern Mediterranean and Asian regions decreased when the women immigrated to a low-frequency region (Denmark). During 70 months, 1,741 pregnant immigrant women referred from primary care to an obligatory hemoglobinopathy screening were eligible for the study, as their screening was negative. To compare this group with a cohort of 205 pregnant ethnic Danish women, the groups were matched by gestational age, and a total of 406 immigrant women were included. Hemoglobin (Hb) and iron status parameters were examined in the two groups. The prevalence of anemia was higher in the immigrant group (20.0%) compared to the Danish women (4.9%) (P < 0.0001). Blood Hb concentration was 119 ± 12 g/l (mean ± SD) in the immigrant group compared to 122 ± 9 g/l in the Danish group (P = 0.01). Erythrocyte mean corpuscular volume (MCV) was also lower in the immigrant group (87 ± 7 fl vs 96 ± 4 fl) (P < 0.0001). A total of 13.1% of the immigrant women had an MCV <80 fl (the lower reference limit) compared to 0.0% in the Danish group, and plasma iron, ferritin, and transferrin saturation values indicated iron deficiency. Conclusively, the pregnant immigrant women had significantly higher prevalence of anemia compared to pregnant women of Danish origin. It indicates the need for an alternative routine screening procedure for this population group, which should also include nutritional counselling.     

Iron stores,response to α-interferon therapy,and effects of iron depletion in chronic hepatitis C

Abstract: We studied 81 patients with chronic hepatitis C to investigate the relationship between iron and α-interferon response. Sixty-one patients (group A) were given α-interferon irrespective of iron status, whereas 20 (group B) with iron overload, were iron depleted before α-interferon therapy. In group A, 21 patients responded to α-interferon and 40 were non-responders. Increased iron indices were significantly more frequent in non-responders than responders. Multivariate analysis showed that among the independent variables evaluated, only γ-GT and liver iron concentration predicted therapy outcome. After phlebotomy treatment, serum alanine aminotransferase fell significantly both in patients of group B (196±122 IU/1 vs 82±37 IU/1, p<10^-6) and in 12 non-responders of group A (198±89 IU/1 vs 107±81 IU/1, p<10^-6). In 16 iron depleted patients, eight from each group, subsequent treatment with α-interferon produced a response in only one patient. These results suggest that increased liver iron is a negative prognostic factor for a-interferon response in chronic hepatitis C. Iron depletion had a beneficial effect on serum alanine aminotransferase in all the patients treated, but did not improve the response to α-interferon.     

Sustained improvements in myocardial T2* over 2 years in severely iron‐overloaded patients with beta thalassemia major treated with deferasirox or deferoxamine

Long‐term controlled studies are needed to inform on the clinical benefit of chelation therapy for myocardial iron removal in transfusion‐dependent beta thalassemia patients. In a 1‐year nonrandomized extension to the CORDELIA study, data collected from patients with myocardial siderosis provided additional information on deferasirox or deferoxamine (DFO) efficacy and safety. Myocardial (m)T2* increased from baseline 11.6 to 15.9 ms in patients receiving deferasirox for 24 months (n = 74; geometric mean [G_mean] ratio of month 24/baseline 1.38 [95% confidence interval 1.28, 1.49]) and from 10.8 to 14.2 ms in those receiving DFO (n = 29; G_mean ratio 1.33 [1.13, 1.55]; P = 0.93 between groups). Improved mT2* with deferasirox was evident across all subgroups evaluated irrespective of baseline myocardial (mT2* < 10 vs. ≥ 10 ms) or liver (LIC <15 vs. ≥15 mg Fe/g dw) iron burden. Mean LVEF was stable and remained within normal limits with deferasirox or DFO. Liver iron concentration decreased from high baseline values of 30.6 ± 18.0 to 14.4 ± 16.6 mg Fe/g dw at month 24 in deferasirox patients and from 36.8 ± 15.6 to 11.0 ± 12.1 mg Fe/g dw in DFO patients. The long‐term safety profile of deferasirox or DFO was consistent with previous reports; serious drug‐related AEs were reported in 6.8% of deferasirox and 6.9% of DFO patients. Continued treatment of severely iron‐overloaded beta thalassemia patients with deferasirox or DFO led to sustained improvements in myocardial iron irrespective of high or low baseline myocardial or liver iron burden, in parallel with substantial improvements in liver iron ( Clinicaltrials.gov identifier: NCT00600938). Am. J. Hematol. 90:91–96, 2015. © 2014 Wiley Periodicals, Inc.     

The Relationship Between High‐Sensitivity C‐Reactive Protein Levels and Left Ventricular Hypertrophy in Patients With Newly Diagnosed Hypertension

The authors aimed to evaluate the relationship between high‐sensitivity C‐reactive protein (hs‐CRP) and presence of left ventricular hypertrophy and diastolic dysfunction in patients with hypertension. A total of 95 newly diagnosed hypertensive patients (mean age, 54±10 years) and 20 controls were included in this study. Patients were divided into four groups according to relative wall thickness as normal, concentric remodeling, concentric, and eccentric hypertrophy. hs‐CRP was measured in all patients and serum hs‐CRP level was shown to be increased in patients with hypertension compared with controls (0.57 mg/dL vs 0.25 mg/dL, respectively; P<.001). The hs‐CRP level was highest in patients with concentric hypertrophy. When compared with controls, serum hs‐CRP level was significantly higher in patients with concentric remodeling (0.61±0.3 mg/dL vs 0.43±0.5 mg/dL, P<.030) and concentric hypertrophy (0.69±0.3 mg/dL vs 0.43±0.5 mg/dL, P<.032). The present study shows that serum hs‐CRP is significantly associated with left ventricular diastolic function and concentric hypertrophy in patients with hypertension.     

Optimal and continuous anaemia control in a cohort of dialysis patients in Switzerland

Background

Guidelines for the management of anaemia in patients with chronic kidney disease (CKD) recommend a minimal haemoglobin (Hb) target of 11 g/dL. Recent surveys indicate that this requirement is not met in many patients in Europe. In most studies, Hb is only assessed over a short-term period. The aim of this study was to examine the control of anaemia over a continuous long-term period in Switzerland.

Methods

A prospective multi-centre observational study was conducted in dialysed patients treated with recombinant human epoetin (EPO) beta, over a one-year follow-up period, with monthly assessments of anaemia parameters.

Results

Three hundred and fifty patients from 27 centres, representing 14% of the dialysis population in Switzerland, were included. Mean Hb was 11.9 ± 1.0 g/dL, and remained stable over time. Eighty-five % of the patients achieved mean Hb ≥ 11 g/dL. Mean EPO dose was 155 ± 118 IU/kg/week, being delivered mostly by subcutaneous route (64–71%). Mean serum ferritin and transferrin saturation were 435 ± 253 μg/L and 30 ± 11%, respectively. At month 12, adequate iron stores were found in 72.5% of patients, whereas absolute and functional iron deficiencies were observed in only 5.1% and 17.8%, respectively. Multivariate analysis showed that diabetes unexpectedly influenced Hb towards higher levels (12.1 ± 0.9 g/dL; p = 0.02). One year survival was significantly higher in patients with Hb ≥ 11 g/dL than in those with Hb <11 g/dL (19.7% vs 7.3%, p = 0.006).

Conclusion

In comparison to European studies of reference, this survey shows a remarkable and continuous control of anaemia in Swiss dialysis centres. These results were reached through moderately high EPO doses, mostly given subcutaneously, and careful iron therapy management.     

Serum Copper,Ceruloplasmin and 24-h Urine Copper Evaluations in Celiac Patients

The aim of the study is to evaluate the serum copper, ceruloplasmin and 24-h urine copper levels in celiac patients.Serum copper, ceruloplasmin and 24-h urine measurements were evaluated in patients with celiac (n = 32), Crohn’s (n = 25), Wilson’s (n = 11) and in a healthy group (n = 35). Serum and 24-h urine zinc levels, AST, ALT, BUN, creatinine, iron, hemoglobin, hematocrit, lymphocyte, sedimentation and CRP levels were also measured. Results were evaluated statistically and significance was accepted as meaningful if P < 0.05. In celiacs, levels of urine copper were high (52 ± 29 μg/day, P < 0.000) but serum copper was the same as in controls (105 ± 16 μg/dl, P < 0.158). High urinary copper of celiacs were coming out in women (56 ± 30 μg/day) and in man (33 ± 17 μg/day, P < 0.115). Most celiacs were female (P < 0.001). Serum copper and ceruloplasmin levels in all groups were higher in women than in men and this was meaningful for serum copper in the control group (P < 0.045) and for ceruloplasmin in Crohn’s (P < 0.055) and control groups (P < 0.031). Serum (70 ± 14 μg/dl, P < 0.000) and urine zinc levels (25 ± 15 μg/dl, P < 0.039) of celiacs were low. Ceruloplasmin levels were higher in celiacs (337 ± 64 U/l) and Crohn’s patients (366 ± 47 U/l, P < 0.000). Correlations observed in the groups of celiac (P < 0.029) and Crohn’s (P < 0.024), celiac and Wilson’s (P < 0.001) and Crohn’s and Wilson’s (P < 0.001) between the ceruloplasmin and 24-h urine copper parameters. AST and ALT levels were higher in celiac and Wilson’s patients than in Crohn’s patients and controls. Mean CRP levels were significantly higher in Crohn’s than others. Lymphocyte counts were meaningfully higher in celiacs. Statistically, while mean iron, hemoglobulin and hematocrit levels of celiac and Crohn groups were meaningfully lower than the normal and Wilson’s group, it was similar in Wilson’s and the control group. Serum copper (85 ± 26 μg/dl, P < 0.158) and ceruloplasmin (219 ± 83 U/l, P < 0.001) levels were low and 24-h urine copper levels were high (415 ± 346 μg/day) in Wilson’s group. Increased urinary loss may be another cause of copper deficiency in female celiacs besides malabsorption and this topic needs more investigation. Increased urinary copper levels in celiac women should not always be regarded as a diagnosis of Wilson’s disease.     

Response to hydroxycarbamide in pediatric β-thalassemia intermedia: 8 years’ follow-up in Egypt

Hydroxycarbamide (hydroxyurea or HU) has been shown to increase fetal hemoglobin (HbF) in patients with β-thalassemia intermedia (TI). The reported effects of HU in increasing the total hemoglobin (Hb) have been inconsistent. Studies of long-term therapy with HU in pediatric TI are rather uncommon. A retrospective observational study was carried out to evaluate the clinical responses to HU in Egyptian patients with β-TI. One hundred patients; children (n?=?82, mean age 9.9?±?4.1 years) and adults (n?=?18) were studied for the mean Hb, HbF%, median serum ferritin, transfusion history, and splenic size before and after HU therapy (mean dose 20.0?±?4.2 mg/kg/day, range 10–29 mg/kg/day) over a follow-up period 4 to 96 months (mean 35.4?±?19.2 months). Molecular studies were also done for group of patients (n?=?42). The overall response rate to HU was 79 %; 46 % were minor responders (with a reduction in transfusion rate by 50 % or more and/or an increase in their total hemoglobin level by 1–2 g/dl) and 33 % major responders (becoming transfusion-free and/or having an increase in total hemoglobin level by >2 g/dl). Mean hemoglobin increased among responders from 6.9?±?0.9 g/dl to 8.3?±?1.4 g/dl (p?p?p?n?=?45). Transfusions stopped in 44 % of pretreatment frequently transfused responders (n?=?11/25). Splenic size decreased in 37 % of patients (n?=?30/81). The predominant β-thalassemia mutation was 1–6 (T?>?C) in 32/42 (76 %) of studied patients; 28/32 were responders. Bivariate analysis showed no predictors of response as regards sex, pediatric and adult age, splenic status, or genotype. Hydroxycarbamide is a good therapeutic modality in the management of pediatric as in adult TI patients. It can minimize the need for blood transfusion, concomitant iron overload, and blood-born viral transmission especially in developing countries like Egypt.     

Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency.

OBJECTIVES: Our objective was to evaluate in a double-blind, randomized, placebo-controlled study possible modifications in NT-pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) levels together with clinical and functional parameters, in a group of anemic patients with chronic heart failure (CHF) and chronic renal failure (CRF) receiving intravenous iron therapy, without recombinant human erythropoietin (rhEPO), versus placebo. BACKGROUND: Chronic heart failure and CRF associated with absolute or relative iron deficiency anemia is a common problem. This situation is linked with a variable inflammatory status. Both NT-proBNP and CRP are recognized markers for left ventricular dysfunction and inflammatory status, respectively. In this double-blind, randomized, placebo-controlled study, modifications in NT-proBNP and CRP level and clinical and functional parameters, in anemic patients with CHF and CRF receiving intravenous iron therapy, without rhEPO, versus placebo were evaluated. METHODS: Forty patients with hemoglobin (Hb) <12.5 g/dl, transferrin saturation <20%, ferritin <100 ng/ml, creatinine clearance (CrCl) <90 ml/min, and left ventricular ejection fraction (LVEF) < or =35% were randomized into 2 groups (n = 20 for each). For 5 weeks, group A received isotonic saline solution and group B received iron sucrose complex, 200 mg weekly. Minnesota Living with Heart Failure Questionnaire (MLHFQ) and 6-min walk (6MW) test were performed. NT-pro brain natriuretic peptide and CRP were evaluated throughout the study. No patients received erythroprotein any time. RESULTS: After 6 months follow-up, group B showed better hematology values and CrCl (p < 0.01) and lower NT-proBNP (117.5 +/- 87.4 pg/ml vs. 450.9 +/- 248.8 pg/ml, p < 0.01) and CRP (2.3 +/- 0.8 mg/l vs. 6.5 +/- 3.7 mg/l, p < 0.01). There was a correlation initially (p < 0.01) between Hb and NT-proBNP (group A: r = -0.94 and group B: r = -0.81) and after 6 months only in group A: r = -0.80. Similar correlations were observed with Hb and CRP. Left ventricular ejection fraction percentage (35.7 +/- 4.7 vs. 28.8 +/- 2.4), MLHFQ score, and 6MW test were all improved in group B (p < 0.01). Additionally, group B had fewer hospitalizations: 0 of 20 versus group A, 5 of 20 (p < 0.01; relative risk = 2.33). CONCLUSIONS: Intravenous iron therapy without rhEPO substantially reduced NT-proBNP and inflammatory status in anemic patients with CHF and moderate CRF. This situation was associated with an improvement in LVEF, NYHA functional class, exercise capacity, renal function, and better quality of life.     

Associations of Peritoneal Glucose Load With Male Sexual Dysfunction and Depression in Peritoneal Dialysis Patients

This cross‐sectional study examined possible associations of peritoneal glucose load with male sexual dysfunction and depression in peritoneal dialysis patients. Compared to patients with peritoneal glucose load ≤3 g/kg per day, those with load >3 g/kg per day had higher Beck Depression Inventory scores, (18.9 ± 5.4 vs. 11.4 ± 5.8, P = 0.002) and lower International Index of Erectile Function scores, serum total testosterone and DHEA [(15.4 ± 6.4 vs. 45.1 ± 20.7, P < 0.001), (8.5 ± 3.0 vs. 13.9 ± 3.2, P < 0.001), (113.9 ± 58.8 vs. 280.2 ± 128.3, P < 0.001); respectively)]. Of participants with peritoneal glucose load >3 g/kg per day, 84.6% had mild to moderate erectile dysfunction and 92.3% had abnormal Beck Depression Inventory scores. Peritoneal glucose load inversely correlated with International Index of Erectile Function scores (P < 0.001), total serum testosterone (P = 0.002) and serum DHEA (P = 0.001); and directly with Beck Depression Inventory scores (P < 0.001) and serum estradiol (P < 0.001). This study demonstrated higher prevalence of sexual dysfunction, depression and sex hormone disturbances in male peritoneal dialysis patients receiving higher peritoneal glucose load.     

Correlation Between Inflammation and Oxidative Stress in Normocholesterolemic Coronary Artery Disease Patients ‘on’ and ‘off’ Atorvastatin for Short Time Intervals

Summary Aim of the study: To assess whether variations in antioxidant and anti-inflammatory parameters occur with short term administration and discontinuation of atorvastatin in normocholesterolemic coronary artery disease (CAD) patients. Methods: Forty CAD patients with near normal serum cholesterol levels (total cholesterol <240 mg/dl, LDL cholesterol <130 mg/dl) were continuously enrolled and randomized to groups A & B (20 patients taking atorvastatin) and groups C & D (20 patients not taking atorvastatin). Atorvastatin (10 mg/day) was continued in group A, withdrawn in group B and started in groups C & D for 6 weeks. Thereafter atorvastatin was withdrawn in group A and C, restarted in group B, and continued in group D for further 6 weeks. CRP, FRAP and TBARS were assessed at baseline, 6 weeks and 12 weeks in all the groups. Results: Baseline CRP, TBARS and FRAP levels were significantly different (p < 0.05) between groups A & B and C & D at the time of enrollment, indicating lower levels of oxidative stress (FRAP—172.40 ± 23.41 nmol Fe²⁺/l vs 142.62 ± 15.73 nmol Fe²⁺/l and TBARS—3.66 ± 1.14 nmol/ml vs 6.11 ± 1.85 nmol/ml) and low grade inflammation (CRP—1.38 ± 0.69 mg/l vs 3.19 ± 1.77 mg/l) in statin treated groups. In group B, discontinuation resulted in increase in CRP (2.87 ± 0.98 mg/l) and TBARS (5.75 ± 1.35 nmol/ml) and decrease in FRAP (133.132 ± 13.32 nmol Fe²⁺/l) and whereas group A patients did not show significant variation in values compared to baseline (CRP—1.36 ± 0.33 mg/l, FRAP—155.45 ± 19.51 and TBARS—4.22 ± 0.81). Administration of atorvastatin caused a marked reduction in oxidative stress and inflammation in groups C & D (CRP—1.13 ± 0.99 mg/l & 1.73 ± 1.60 mg/l, FRAP—166.54 ± 34.11 & 177.44 ± 13.31 nmol Fe²⁺/l, TBARS—4.66 ± 2.33 & 3.55 ± 1.25 nmol/ml respectively). The values returned to pretreatment levels on discontinuation of the drug in group C (CRP—2.61 ± 1.28 mg/l, FRAP—138.49 ± 19.62 nmol Fe²⁺/l, TBARS—6.13 ± 0.74 nmol/ml) whereas the decline was maintained in group D (CRP—1.62 ± 1.48 mg/l, FRAP—173.07 ± 9.03 nmol Fe²⁺/l, TBARS—3.75 ± 1.03 nmol/ml). Conclusion: Administration and withdrawal of atorvastatin caused changes in markers of oxidative stress which closely correlated with changes in marker of inflammation. Further, the salutary effects were of quick onset, but were rapidly reversed on withdrawal of atorvastatin.     

Serum levels of tumour necrosis factor-α predict response to recombinant human erythropoietin in patients with myelodysplastic syndrome

Summary We measured pretreatment serum levels of tumour necrosis factor-α (TNF-α) and interleukin-1β(IL-1β) in 25 patients with myelodysplastic syndrome receiving recombinant human erythropoietin (rhEPO) at dosages up to 300 U/kg thrice weekly for 12 weeks. Both TNF-α and IL-1β levels were measured using commercially available enzyme-linked immunoassays. A complete response (CR) was defined as a rise in untransfused haemoglobin concentrations of at least 2 g/dl or a 100% decrease in RBC transfusion requirements over the treatment period; a partial response (PR) was an increase in untransfused haemoglobin values of 1–2 g/dl or a decrease in RBC transfusion requirements equal to or greater than 50%; no response (NR) was defined as a response less than a PR. After 12 weeks of rhEPO treatment, four patients showed a CR, five patients a PR, and 16 patients NR. Serum levels of both TNF-α (80.5 ± 64.8 vs 8.1 ± 4.2 ng/l, P < 0.001) and IL-1β (60.4 ± 49.9 vs 8.9 ± 4.7 ng/l, P < 0.001) were higher in MDS patients than in a group of 28 normal controls. Responders (CR + PR) showed significantly lower serum levels of TNF-α than non-responders (21.6 ± 26.2 vs 106.3 ± 60.8 ng/l, P < 0.001), whereas IL-1β concentrations between those who benefited from therapy and unresponsive cases were not significantly different (39.8 ± 48.9 vs 73.4 ± 48.2 ng/l, P= 0.120). It is noteworthy that TNF-α levels were within the normal range in all responsive patients but one, whereas all non-responders presented elevated cytokine concentrations. No relationship was found between TNF-α or IL-1β values and haemoglobin levels, transfusion requirement, serum EPO or ferritin concentrations. We conclude that pre-treatment TNF-α levels might help to select those MDS patients who are most likely to benefit from rhEPO treatment.     

Anemia in Crohn's disease

Intestinal blood loss as well as chronic inflammation are regarded as the most important mechanisms in the pathogenesis of anemia in Crohn's disease. In addition, cytokines such as interleukin-6 can suppress erythropoietin production. This study was performed to investigate the importance of iron status, inflammatory activity, and endogenous erythropoietin concentrations for the development of anemia in Crohn's disease. In 49 consecutive patients with Crohn's disease, hemoglobin, inflammatory activity (Crohn's disease activity index, C-reactive protein, α₁-acid glycoprotein), iron status (serum iron, transferrin, transferrin saturation, ferritin), and serum erythropoietin levels were studied. Anemic (Hb<12.0 g/dl;N=16) vs nonanemic patients (Hb≥12 g/dl;N=33) showed reduced iron compartments (eg, ferritin 28.7±12.9 µg/liter vs 63.2±15.0 µg/liter, transferrin saturation 6.2±1.4% vs 11.5±1.3%,P<0.01) but no differences in inflammatory activity. An inverse correlation between erythropoietin and hemoglobin concentrations was found (r=-0.62;P<0.001), but the increase in erythropoietin levels was inadequate to the degree of anemia. There was no correlation between erythropoietin and interleukin-6 serum levels. Four of five anemic patients with hemoglobin below 10.5 g/dl and erythropoietin levels within the normal range were treated with parenteral iron (200 mg iron saccharate in 250 ml NaCl, weekly, intravenously). Two of them additionally received recombinant human erythropoietin (150 units/kg, 3× weekly, subcutaneously). After five weeks all patients had a marked increase in hemoglobin. However, the mean increase in erythropoietin-treated patients was 5.0 g/dl compared to 2.0 g/dl in the patients with iron therapy only. No side effects were seen. Our data demonstrate that inadequate erythropoietin production and iron deficiency are pathogenetic factors of anemia in Crohn's disease. The therapeutic management using recombinant human erythropoietin and parenteral iron is reasonable and effective.