Effectiveness of erythropoiesis on supervised intradialytic oral iron and vitamin C therapy is correlated with Kt/V and patient weight

BACKGROUND: Poor compliance to oral medication and diet is common in hemodialysis (HD) patients and limits the ability of oral iron therapy to support erythropoiesis. Intravenous (i.v.) iron may be associated with undesirable and sometimes life-threatening complications. PATIENTS AND METHODS: We hypothesized that intradialytic oral iron therapy can overcome compliance problems and support effective maintenance erythropoiesis, which will keep Hct in the range of 33% to 36% and EPO requirements up to 50 units/week/kg. In a prospective observational study, SC EPO-treated hospital-based HD patients without conditions known to cause EPO resistance, were managed on intradialytic oral administration of iron and vitamin C. The primary endpoints were EPO requirements and resistance to EPO which standardized EPO requirements by the Hct level. Secondary endpoints included parameters that might affect the primary endpoints. Exclusion criteria were refusal to take oral medication, prestudy Hct < 27%, recent i.v. iron therapy or transfusions, bleeding, clinical conditions obligating Hct > 30% and known causes of EPO resistance. Twelve patients completed minimal follow-up period of 9 months. RESULTS: Mean Hct was 34.4% (range: 31.8% - 40.2%). EPO requirements were 61.7 +/- 28.2 units/kg and below 52.5 units/kg in 50% of patients. Patients were classified into equal groups according to resistance to EPO, which was positively correlated (r = 0.71 p < 0.01) with body weight and Kt/V (r = -0.38, p < 0.05). CONCLUSION: In conclusion, intradialytic oral iron therapy can support effective maintenance erythropoiesis in 50% of patients without known causes for EPO resistance. High response to EPO and low EPO requirement are correlated with lower body weight and possibly improved dialysis.     

Skeletal effects of erythropoietin in hemodialysis patients

AIMS: To assess the effects of erythropoietin (EPO) on bone metabolism in patients receiving chronic hemodialysis (HD). METHODS: Forty one patients were divided into two groups whether they required the administration of EPO to treat renal anemia or not. Serial measurements of predialysis blood samples and bone mineral density were performed prospectively over a year. RESULTS: The administration of EPO was associated with an increased serum creatinine (11.9 +/- 0.4 to 12.5 +/- 0.4 mg/dl, p < 0.05), insulin-like growth factor binding protein (3.0 +/- 0.2 to 3.4 +/- 0.2 micrograms/ml, p < 0.05) as well as decreased iron level (112 +/- 7 to 88 +/- 7 micrograms/dl, p < 0.005). Furthermore, in EPO-treated group, exogenous EPO doses correlated with the increments in 1,25-dihydroxy-vitamin D (r = 0.38, p < 0.05), intact osteocalcin (r = 0.42, p < 0.05) and bone alkali-phosphatase (r = 0.53, p < 0.005), but not intact parathyroid hormone (r = 0.09). Both metacarpal index (0.47 +/- 0.02 to 0.47 +/- 0.02) and the summation of gray scale/diameter (2.68 +/- 0.06 to 2.61 +/- 0.07 mmAl), bone mineral density parameters, remained unchanged. CONCLUSION: The present data provide evidence that EPO may modulate the production of 1,25-dihydroxy-vitamin D in HD patients. Furthermore, our findings suggest that EPO therapy activates insulin-like growth factor system in HD patients, possibly through its actions on metabolism.     

Iron deficiency is a common cause of anemia in chronic kidney disease and can often be corrected with intravenous iron

BACKGROUND: There is some epidemiological and clinical evidence that the anemia seen in chronic kidney disease (CKD) in patients not on dialysis could be due to a significant extent to iron deficiency, and that adequate iron replacement could cause a marked improvement in the anemia even without the use of erythropoietin (EPO). The purpose of this work was to study the effects of intravenous (i.v.) iron administration (ferric gluconate - Ferrlecit) on hemoglobin (Hb) of patients with CKD. METHODS: Forty-seven consecutive patients with CKD with Hb <12 g/dL in whom no underlying cause for the anemia could be found underwent sternal bone marrow biopsy and had their red cell and blood iron parameters measured. They then received 250 mg of ferric gluconate (Ferrlecit) intravenously twice monthly for 3 months, and had their blood parameters measured 1 month later. No patient received erythropoietin (EPO). RESULTS: Forty-six patients had no evidence of any iron deposits in the bone marrow - consistent with the presence of severe iron deficiency. The mean serum ferritin and %transferrin saturation prior to treatment were 235.9 +/- 54.3 ug/L and 13.5 +/- 4.1%, respectively, and both increased significantly with the iron treatment. Mean Hb increased from 10.16 +/- 1.32 to 11.96 +/- 1.52 g/dL, an increase of 1.80 +/- 1.72 g/dL (p<0.01). Twenty-six patients (55.3%) reached the target Hb of 12 g/dL. Ten patients (21.3%) had an increase of 0.1-0.9 g/dL, nine patients (19.1%) had an increase of 1-1.9 g/dL and 23 patients (48.9%) had an increase of >or= 2 g/dL. CONCLUSIONS: Iron deficiency is frequently seen in anemic CKD patients not on dialysis and its correction with i.v. iron will often cause a marked increase in the Hb level, and the achievement of the target Hb of 12 g/dL even without EPO.     

Effects of erythropoietin treatment on cell-mediated immune responses in predialysis patients

OBJECTIVE: The effects of erythropoietin (EPO) treatment on the immune functions of dialysis patients have been shown to be controversial and there are only limited data concerning predialysis patients. MATERIAL AND METHODS: Twenty-four predialysis patients with renal anemia were assigned to subcutaneous EPO treatment, and those in need (n=19) were additionally treated with i.v. iron every other week. We analyzed the effect of the start of EPO treatment on (i) lymphocyte and lymphocyte subclass counts, (ii) lymphocyte stimulation functions and (iii) persisting IgG-class antibody levels to the viral antigens of Epstein-Barr virus and cytomegalovirus. RESULTS: Our main findings were a decrease in the absolute lymphocyte count, combined with decreases in all the main lymphocyte subclass counts. The absolute number of cells with activation and memory markers remained constant, and therefore their proportion slightly increased. The proliferation responses to phytohemagglutinin, tuberculin and tetanus declined significantly, while the amount of IgG-class viral antibodies remained unchanged, meaning that the humoral side of immunity was not affected by the start of the EPO treatment. Similarly, the proliferation response to pokeweed mitogen, a B-cell mitogen, was unchanged. CONCLUSIONS: EPO treatment has a suppressive effect on cellular immune functions of predialysis patients. This suppression does not correlate with erythropoiesis, kidney function or iron status.     

Chronic peritoneal dialysis in iron-deficient rats with solutions containing iron dextran

BACKGROUND: We evaluated the effects of different concentrations of iron dextran administered through the intraperitoneal route, in iron-deficient rats, on hematocrit (Hct in percentage), serum iron (mg/dL), total iron binding capacity (TIBC in mg/dL), and the function and histology of the peritoneal membrane. METHODS: Seventy-two male Sprague-Dawley rats weighing 85 to 110 g were divided into two groups and seven subgroups. Group I consisted of rats on iron-deficient chow, and group II consisted of rats on normal chow. Both groups contained dialysis control subgroups (N = 12: IA, IID), dialyzed with Dianeal solution, and tissue control subgroups (N = 6: IE, IIN), in which rats were not dialyzed and catheters were not implanted. Study group I contained the following study subgroups (N = 12): (B) rats dialyzed with Dianeal solution containing 2 mg/L of iron dextran and (C) rats dialyzed with Dianeal solution containing 1 mg/L of iron dextran. Group IID was dialyzed with Dianeal solution containing 2 mg/dL of iron dextran. Study duration was 12 weeks with peritoneal equilibration tests (PETs) performed at baseline, 6 weeks, and 12 weeks. Prior to baseline, rats were placed on iron-deficient chow or normal chow for three weeks. Dialysis was performed with three 25 mL volume exchanges per day. Hematocrit (Hct), serum iron (Fe), and total iron binding capacity (TIBC) were determined for each study interval. After the final PET, the animals were sacrificed, and the peritoneal membrane was evaluated by gross inspection and light microscopy. RESULTS: Rats on an iron-deficient diet developed severe iron-deficiency anemia after three weeks of the diet (Hct 27; Fe 21 to 23; TIBC 799 to 806). After 12 weeks, the rats remained anemic in groups A (Hct 34 +/- 0.9; Fe 16 +/- 2; TIBC 998 +/- 27) and IE (Hct 38 +/- 2.7), whereas the rats corrected anemia in group B (Hct 45.8 +/- 1.8; Fe 115 +/- 15; TIBC 546 +/- 77). The results were not significantly different from those of group IID (Hct 47.1 +/- 1.6; Fe 94 +/- 19; TIBC 516 +/- 46). In group C, Hct (44.8 +/- 2.1) and Fe (94 +/- 19) did not differ significantly from group IID, but TIBC (734 +/- 76) remained significantly higher than that in the group IID. Peritoneal iron deposits were not detected. The morphometric analysis of the submesothelial space did not reveal any difference in thickness between dialysis groups. PETs were not significantly different among groups. CONCLUSIONS: Intraperitoneal iron dextran supplementation in concentrations of 2 mg/L of dialysis solution is nontoxic to the peritoneum and effective in correcting iron deficiency in rats maintained on an iron-deficient diet. Iron dextran in concentration of 1 mg/L of dialysis solution may be sufficient for correcting a lesser degree of iron deficiency.     

The evaluation of postdialysis L-carnitine administration and its effect on weekly requiring doses of rHuEPO in hemodialysis patients

BACKGROUND: In this study, our aim was to evaluate the effect of postdialysis administration of parenteral L-carnitine supplementations on hematological parameters and also on weekly requiring dose of the recombinant human erythropoietine (rHuEPO) in hemodialysis (HD) patients. MATERIAL AND METHODS: The stable 34 patients (17 male, 17 female) were enrolled in the study who were on rHuEPO therapy and a regular maintenance HD program at 5 h, three times a week with bicarbonate dialysate and with biocompatible membranes in HD Center of Medical Faculty Hospital in University of Dicle. rHuEPO was administered subcutanously at 80-120 U/kg/week. The patients were divided into two groups: Group 1, rHuEPO therapy (n=17) and Group 2, rHuEPO therapy + L-carnitine (n=17). L-carnitine (L-carnitine ampul, Santa Farma) 1 g was injected postdialysis intravenously via venous route of the dialytic set, three times a week. The patient's hemoglobin (Hgb), hematocrit (Hct), serum iron (Fe(+2)), total iron-binding capacity (TIBC), transferrin saturation index (TSI), and serum ferritin (Fer) levels were followed during the 16-week period. The weekly requiring doses of rHuEPO and hematological parameters of patients were recorded at the beginning of the study, at 8 weeks, and at 16 weeks of the study period. RESULTS: In group 1 (n=17, 13 female, four male), the mean age was 38.8 +/- 12.1 years, mean period time on HD therapy was 18.1 +/- 14.9 months, and mean Kt/V value was 1.48 +/- 0.28. In group 2 (n=17, 13 male, four female), the mean age was 48.1 +/- 15.4 years, mean period time on HD therapy was 34.4 +/- 23.0 months, and mean Kt/V value was 1.29 +/- 0.20. The hematological parameters of the groups were found as follows: in group 1, Hgb: 7.9-10.8 g/dl, Hct: 25.3-32.5%; in group 2, Hgb: 10.2-11.8 g/dl, Hct: 30.6-35.4%, respectively (p < 0.05). The target Hgb/Hct values were achieved at the end of the study in both groups. Both groups were the same according to their serum Fe(+2) markers (p > 0.05). But unlike serum Fe(+2) markers, there were significant differences on weekly requiring doses of rHuEPO therapy between groups. While in group 1, the mean weekly requiring dose of rHuEPO was 6529 U/week (120 U/kg/ week) at the beginning of the study, and maintenance weekly requiring dose of rHuEPO was 3588 U/week (66 U/kg/week) at the end of the study, in group 2, they were 4882 U/week (80 U/ kg/week), and 1705 U/week (28 U/kg/week), respectively. According to these values, the total reduction in weekly requiring dose of rHuEPO was 45% in group 1, and 65% in group 2; the net gain was 20% in group 2 (p < 0.05). CONCLUSIONS: If other factors related to anemia are excluded, the postdialysis parenteral L-carnitine therapy can be considered in selected stable patients, which may improve anemia and may reduce the weekly requiring dose of the rHuEPO and also be cost-effective.     

Soluble transferrin receptors and reticulocyte hemoglobin concentration in the assessment of iron deficiency in hemodialysis patients

BACKGROUND: Diagnosing iron deficiency in hemodialysis (HD) patients is crucial for correct anemia management. Hypochromic erythrocytes appear to be the best available marker, but they are often unavailable. Transferrin saturation (TSAT) and ferritin are also indicated as reference markers by guidelines. We evaluated the usefulness of soluble transferrin receptor (s-TfR) and reticulocyte hemoglobin concentration (CHr), which have been recently proposed as more sensitive functional iron deficiency indicators. METHODS: A single-center unselected cohort of 39 chronic HD patients underwent a cross-sectional determination of hemoglobin (Hb), hematocrit (Hct), CHr, transferrin, iron, TSAT, ferritin, folate, vitamin B12 and s-TfR. Twenty-nine patients (74.4%) were treated with subcutaneous erythropoietin (EPO) at a dose of 122 +/- 98 U/kg/week and 24 patients (61.5%) were treated with intravenous (i.v.) iron gluconate, 62.5 mg/week. RESULTS: Hb was 11.1 +/- 1.2 g/dL, Hct 34.4 +/- 3.7%, CHr 32.7 +/- 3.8 pg, transferrin 170 +/- 31 mg/dL, iron 60.2 +/- 25.9 mg/dL, TSAT 30 +/- 18%; ferritin 204 +/- 219 ng/mL, folate 4.2 +/- 1.0 mcg/L, vitamin B12 0.58 +/- 0.15 mcg/L, and s-TfR 1.94 +/- 0.83 mg/L. Both TSAT and s-TfR significantly correlated with CHr, but no relationship could be found between s-TfR and TSAT or between s-TfR and ferritin. Dividing the population into two groups based on iron repletion (ferritin >100 ng/mL and TSAT >20%) we found no differences for CHr levels and significantly lower levels of s-TfR in the replete group (s-TfR 1.71 +/- 0.70 vs. 2.29 +/- 0.90 mg/L; p=0.033). Analysis of 2x2 tables demonstrated that 44% of patients with TSAT >20% had elevated (>1.5 mg/L) s-TfR, indicating a possible functional iron deficiency, but covariance analysis showed that TSAT had a better correlation to CHr. CONCLUSIONS: No clear-cut advantages in the use of CHr content and s-TfR levels as single diagnostic tests could be demonstrated by this cross-sectional study. However, our results suggest that the combined use of TSAT <20% and s-TfR >1.5 mg/L (therefore, including all patients with low TSAT, but also patients with high s-TfR despite normal TSAT) could improve functional iron deficiency detection in dialysis patients suspected of having inflammatory conditions.     

Serum erythropoietin levels and their correlation with the erythropoietic system in hemodialysis patients and renal allograft recipients

BACKGROUND: Following renal transplantation, serum erythropoietin (EPO) levels gradually increase during the first 2 to 3 months. However, some transplant recipients continue to remain anemic. The aim of the present study was to correlate serum EPO concentrations with hematocrit (Hct) and hemoglobin (Hb) levels in hemodialysis (HD) patients and renal allograft recipients. METHODS: In a comparative cross-sectional study, serum EPO concentrations and Hb and Hct levels were measured in 35 chronic HD patients and 40 transplant recipients who had stable kidney function for at least 6 months after transplantation (group 1). The HD patients were further divided based on their recombinant human (rHu) EPO supplementation into those who received rHu EPO during dialysis (group 2A, n=15) and those who were not on rHu EPO (group 2B, n=20). Data are presented as mean values +/- SD. The statistical analysis was performed by SPSS version 11.0 using chi-square, ANOVA, and Pearson correlation tests. A general linear model (GLM) was used to compensate for the effects of age. The P value for significance was set at .05. RESULTS: Group 2B patients tended to be older than groups 1 and 2A (P=.014). The sex ratios were comparable among groups. Mean EPO level was 17.09 +/- 10.99 mIU/mL in recipients, which was comparable with that of HD patients (18.54 +/- 26.18 mIU/mL; P>.05). No significant correlation was observed between the serum EPO concentrations and Hb and Hct levels in recipients (P>.05). When comparing the 3 groups, EPO was not correlated with Hct and Hb in any group. Hb and Hct were significantly higher among HD patients not on rHu EPO therapy (P=.02). GLM, with age as a covariate, did not yield a significant difference between EPO levels of the studied groups (P=.36). CONCLUSIONS: This study showed that serum EPO level was in the normal range in recipients and HD patients. We were not able to find any correlation between Hb and Hct levels and EPO concentrations in any group of patients irrespective of rHu EPO supplementation. Hence, impaired EPO stimulatory effects may be considered a potential contributor to anemia in these patients.     

Iron and oxidative stress in renal insufficiency

BACKGROUND/AIMS: Iron (Fe) can cause tissue injury and oxidative stress by catalyzing hydroxyl radical production and lipid peroxidation. Intravenous (i.v.) Fe preparations are routinely administered to treat anemia in patients with chronic renal failure (CRF), a condition marked by oxidative stress and inflammation. In an earlier study, we showed that iron overload augments oxidative stress in the cardiovascular tissues of CRF rats. This study was designed to expand these observations to other major organs. METHODS: Rats were randomized into CRF (5/6 nephrectomized) and sham-operated control (CTL) groups. Each group was subdivided into Fe-loaded (single i.v. injection of iron dextran complex, 0.5 g/kg) and placebo-treated subgroups. After 13 weeks, systolic blood pressure, blood hemoglobin (Hb), plasma Fe concentration, lipid peroxidation products, superoxide generating enzyme, NAD(P)H oxidase, and antioxidant enzymes were determined. RESULTS: Systolic blood pressure was equally elevated and creatinine clearance was equally reduced in both CRF groups. Fe administration raised Hb, serum Fe and transferrin saturation in both CRF and CTL groups. The plasma concentration of lipid peroxidation product, malondialdehyde, was increased by Fe injection in CRF rats but not the control group. Renal tissue abundance of gp91(phox) subunit of NAD(P)H oxidase was elevated in the untreated CRF group and was partially reduced in the iron dextran-treated CRF group. Tissue abundance of the antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) were decreased in both untreated and iron dextran-treated CRF groups. CONCLUSION: CRF resulted in marked SOD, CAT and GPX deficiencies. A single i.v. administration of iron dextran in rats with CRF induced oxidative stress as measured by increased lipid peroxidation products and decreases in antioxidant enzymes.     

Measuring the content of reticulocyte hemoglobin (CHr) in predialysis chronic renal failure (CRF) patients

We showed that the content of reticulocyte hemoglobin (CHr) is a reliable measure of iron status with regard to erythrocytopoiesis in chronic dialysis status. The mean CHr level was 32.3 +/- 2.2 pg in dialysis patients and CHr was significantly correlated with the conventional parameters of iron deficiency. We aimed to utilize the measurement of CHr levels to monitor iron status in clinical practice. We measured CHr, iron parameters, and the intrinsic EPO concentration in non-dialysis CRF patients to clarify the alterations in CHr levels that occur as renal anemia progresses. CRF patients who visited our out-patient clinic (n = 189) were included in the study. Iron deficiency was defined by the transferrin saturation and ferritin levels. Conventional red blood cell parameters and CHr levels were measured using an ADVIA120 autoanalyzer (Bayer Medical, USA). The mean CHr value of the non-dialysis patients (creatinine clearance less than 70 ml/min) was 32.7 pg, which did not differ significantly from that of the dialysis patients. Significant correlations were found between CHr and TSAT (r = 0.032, p < 0.0177), unlike the correlation with intrinsic EPO levels. Overall, 11% of the patients were diagnosed as having iron deficiency. There was a positive correlation between CHr and serum creatinine levels. Non-dialysis CRF patients treated with rHuEPO at the dose of 24,000 U/month showed different CHr levels compared with other patients (less than 24,000 U/month). It is possible that rHuEPO treatment in non-dialysis patients affects iron dynamics. In conclusion, CHr is an easily measurable and reliable marker of iron status in non-dialysis CRF patients. Moreover, the CHr level was also sensitive to iron alternations in non-dialysis CRF patients under rHuEPO treatment. Accordingly, if long-acting EPO is available for non-dialysis CRF patients, the CHr value is likely to be indicative of the need for iron supplementation.     

Experience of iron saccharate supplementation in haemodialysis patients treated with erythropoietin

SUMMARY: We assessed the efficacy of intravenous (i.v.) iron saccharate (VENOFER) vs oral iron supplementation in haemodialysis patients treated with low-dose erythropoietin (EPO). Twenty haemodialysis patients with serum ferritin >200 ng/mL and transferrin saturation >30% were assigned to one of the two groups. In Group 1, 10 were given i.v. iron saccharate (100 mg i.v. twice weekly) post dialysis. In Group 2, oral ferrous sulphate 200 mg was given thrice daily. In both groups, subcutaneous EPO 25 units/kg body weight (BW) was started simultaneously, twice weekly. After 3 months (study completion) the mean haemoglobin and haematocrit was significantly increased in Group 1 than in Group 2 (Hb 11.60 ± 0.64 G/ dL vs 10.5 G/dL ± 1.14 P <0.01). the final mean EPO dose was 25% lower in Group 1 than in Group 2 (3400 ± 1356 U/week vs 4600 ± 1356 U/week P =0.10) and the mean serum ferritin was higher in the i.v. iron group than the oral group (671 ng/mL ± 388 vs 367 ng/mL ± 238 P =NS). the same was also observed with transferrin saturation (44.6%± 19.8 in Group 1 vs. 29%± 11.0 in Group 2 P =NS). No adverse effects were seen during the study. In conclusion, we observed that regular use of i.v. iron had a significantly enhanced haemoglobin response, better maintained serum ferritin and lower EPO dosage requirement than the oral iron group.     

Experience of iron saccharate supplementation in haemodialysis patients treated with erythropoietin

We assessed the efficacy of intravenous (i.v.) iron saccharate (VENOFER) vs oral iron supplementation in haemodialysis patients treated with low-dose erythropoietin (EPO). Twenty haemodialysis patients with serum ferritin >200 ng/mL and transferrin saturation >30% were assigned to one of the two groups. In Group 1, 10 were given i.v. iron saccharate (100 mg i.v. twice weekly) post dialysis. In Group 2, oral ferrous sulphate 200 mg was given thrice daily. In both groups, subcutaneous EPO 25 units/kg body weight (BW) was started simultaneously, twice weekly. After 3 months (study completion) the mean haemoglobin and haematocrit was significantly increased in Group 1 than in Group 2 (Hb 11.60±0.64 G/dL vs 10.5 G/dL±1.14 P <0.01). The final mean EPO dose was 25% lower in Group 1 than in Group 2 (3400±1356 U/week vs 4600±1356 U/week P =0.10) and the mean serum ferritin was higher in the i.v. iron group than the oral group (671 ng/mL±388 vs 367 ng/mL±238 P =NS). The same was also observed with transferrin saturation (44.6%±19.8 in Group 1 vs. 29%±11.0 in Group 2 P =NS). No adverse effects were seen during the study. In conclusion, we observed that regular use of i.v. iron had a significantly enhanced haemoglobin response, better maintained serum ferritin and lower EPO dosage requirement than the oral iron group.     

Recombinant erythropoietin rapidly treats anemia in ischemic acute renal failure

BACKGROUND: The anemia associated with acute renal failure (ARF) is currently treated with blood transfusions, while the anemia of chronic renal failure is treated with recombinant erythropoietin (EPO). We hypothesized that EPO treatment during ARF could rapidly improve hemoglobin levels and be a useful therapeutic approach. In addition, as tubular epithelial cells have EPO receptors that can mediate proliferation, enhanced recovery of renal function may occur with EPO use. METHODS: An established rat model of ischemic ARF was studied, using either moderate or severe ischemia. EPO was administered in a dose of 500 or 3000 U/kg starting at time of ischemia. Hematocrit (Hct), serum creatinine, reticulocyte count, and mortality rate were measured. RESULTS: EPO treatment led to a rapid and significant increase in Hct at 48 and 72 hours after moderate ischemic renal reperfusion injury (IRI) in EPO (500 U/kg)-treated rats compared with control (saline treated) rats (mean +/- SE; 45.6 +/- 0.3% vs. 42.0 +/- 1.0%, P < 0.01) and (46.6 +/- 0.3 vs. 41.0 +/- 1.0, P < 0.01, N = 3 per group). In severe renal IRI, EPO treatment also led to significantly increased Hct at 48 (40.0 +/- 4.4% vs. 36.8 +/- 0.3%, P < 0.01, N = 3 per group) and 72 hours (43.5 +/- 1.5% vs. 34.7 +/- 2.3%, P < 0.01, N = 3 per group). Higher dose (3000 U/kg) EPO led to a more pronounced Hct increase after severe IRI at 48 hours compared with the 500 U/kg dose (43.5 +/- 0.3 vs. 40.3 +/- 0.3, P < 0.01, N = 3 per group). EPO treatment during moderate or severe renal IRI did not change the course of the renal dysfunction. EPO treatment (N = 19) had a significant protective effect on mortality during severe IRI. In addition, loss of body weight during ARF was not affected by EPO therapy. CONCLUSIONS: Recombinant EPO can rapidly increase Hct and improve mortality during ARF. Human studies are warranted to evaluate the clinical applicability of this important finding.     

Erythropoietin requirements: a comparative multicenter study between peritoneal dialysis and hemodialysis

BACKGROUND: The management of anemia with erythropoietin (EPO) is important in the global treatment of dialysis patients. There is a general impression that anemia control with EPO is obtained more easily in peritoneal dialysis (PD) patients than in hemodialysis (HD) patients. The EPO administration route has to be the same to compare the two techniques adequately. METHODS: To compare EPO action by subcutaneous (SC) route in HD and PD, 132 stable patients were recruited (HD: 69, PD: 63) from six centers, with adequate dialysis criteria (Kt/V in HD >1.3; weekly Kt/V in PD >1.8). In a cross-sectional study, the EPO dose/week, the number of EPO doses/week, hemoglobin (Hb), ferritin, transferrin saturation index (TS), albumin and intact parathyroid hormone (iPTH) were analyzed. Iron treatment, comorbidity and ACE inhibitors (ACEI) and angiotensin II antagonist (AIIA) treatment were recorded. A multivariate regression model was used in the statistical analysis. RESULTS: The mean Hb level was the same in both groups, HD 11.6 (1.3) g/dL, PD 11.4 (1.4) g/dL, p=0.3. The SC, EPO doses required to obtain the Hb levels were higher in HD than in PD patients, with a difference of 64.3 u/Kg/week, statistically significant in the multivariate regression model (p=0.001, 95% CI 42.6-86.0). The number of EPO doses/week was also higher in HD patients (65% of HD patients with > or = 3 doses, 19% of PD patients with three or more doses, p<0.001). TS was similar in both groups, while ferritin was higher in HD patients, with a higher percentage of HD patients using intravenous (i.v.) iron (HD 77% vs. PD 49%, p=0.001). Serum albumin and iPTH were lower in PD patients (p<0.001 and p=0.04, respectively), but the percentage of patients with intact parathyroid hormone (iPTH) >500 pg/mL was similar in both groups (HD 17%, PD 14%). CONCLUSIONS: With the same administration route, PD patients showed a reduced EPO requirement, and less frequent EPO administration than HD patients, to obtain the same Hb level. No other factors, except those involved in better depuration of erythropoiesis inhibitors in PD, seemed responsible for the different EPO requirements.     

Total dose infusion iron dextran therapy in predialysis chronic renal failure patients

BACKGROUND: Intravenous iron therapy is now the standard modality of iron supplementation in hemodialysis patients, but its role in predialysis chronic renal failure patients is less well established. The efficacy and safety of intravenous iron dextran as a total dose infusion in predialysis chronic renal failure patients, not receiving erythropoietin was assessed in this study. METHODS: Fifty-six predialysis chronic renal failure patients with anemia, not receiving erythropoietin were included in the study, after obtaining informed consent. Hemoglobin, serum creatinine, creatinine clearance rate and serum ferritin were assessed in all the patients at baseline. Iron dextran in a dose of 1 g dissolved in 500 mL normal saline was administered to all patients as a total dose infusion over 6 h after a prior test dose. Patients were kept in hospital under observation for at least 24 h. All the parameters were repeated in all the patients at 12 weeks and in 21 patients at 1 year. RESULTS: The mean hemoglobin (g/dL) in the patients at baseline and at 12 weeks was 8.28 +/- 0.57 and 9.22 +/- 0.44 respectively (p < 0.001). The mean serum ferritin (ng/mL) increased from 29.73 +/- 9.38 at baseline to 218.43 +/- 15.66 at 12 weeks (p < 0.00001). The mean ferritin value in the 21 patients at 1 year was 136.5 +/- 23.4 (p < 0.01). There were no major adverse events and only minor side effects were observed in 4.9% patients. CONCLUSION: Iron dextran as a total dose infusion corrects anemia in predialysis patients and is an effective method to replenish iron stores. The effect on serum ferritin are evident even at 1 year after the total dose infusion.     

Correction of anemia in uremic rats by intramuscular injection of lentivirus carrying an erythropoietin gene

BACKGROUND: Anemia is an inevitable consequence of chronic renal failure. Gene therapy using lentiviral vector (LV) would be an effective tool to treat anemia associated with renal failure. METHODS: A LV carrying the erythropoietin (EPO) cDNA was administered to skeletal muscle of partially nephrectomized rats, which is a model of uremia. The red blood cell production and serum EPO levels were temporally monitored in these rats. Polymerase chain reaction assays were done to validate the presence of the LV in the experimental rats. RESULTS: After a single intramuscular injection of LV at a dose of 55 microg p24 Gag antigen (approximately 5 x 10(7) transducing units), blood hematocrit (Hct) levels increased and peaked at 3 weeks (47.8 +/- 4.2%, p < 0.01, n = 8) with the levels being maintained for at least 20 weeks (duration of study; 44.9 +/- 3.3%, p < 0.01, n = 3). The control rats receiving LV expressing lacZ had Hct levels of 36.9 +/- 4.1% (n = 8) at 3 weeks and 33.1 +/- 3.7% (n = 4) at 20 weeks, respectively. The serum EPO levels in the rats injected with the LV expression EPO significantly increased (p < 0.01) to 156.3 +/- 3.0 mU/ml compared to the control rats (63.9 +/- 1.7 mU/ml). Polymerase chain reaction analysis of the isolated genomic DNA from the LV-injected rats showed specific positive detection of the LV in only the skeletal muscle tissue at the site of injection, whereas the other tissues, including the liver, spleen, and kidney, were negative. CONCLUSIONS: This study demonstrates that intramuscular injection of LV can produce highly efficient and sustained EPO secretion in uremic rats, and suggests that this approach could be an effective tool to deliver secretable proteins at therapeutic levels in various animal disease models.     

Elderly patients on chronic hemodialysis: Effect of the secondary hyperparathyroidism on the hemoglobin level

In patients on chronic hemodialysis (CHD)hyperparathyroidism (HPTH) is associated withanemia and resistance to erythropoietin (EPO). This study included 86 CHD elderly pts (meanage 74.8 y, mean time on CHD = 50.5 mos); theywere divided into two groups: I (n = 31) – PTH> 250 pg/mL and II (n = 55) – PTH < 250 pg/mL.All these patients had been on CHD for> 6 mos. No differences were found betweengroups in respect to age, sex distribution andtime on CHD. The levels of creatinine, BUN, Ca,Al, Fe, albumin and ferritin were similar.Group I had a higher P level (5.4 vs 4.3 mg/dL,p = 0.001) and Ca x P (53.5 vs 43.7, p =0.009). Also the Hct (31 vs 33.5%, p = 0.008)and the Hb (10.4 vs 11.2 g/dL, p = 0.009) values werelower in Group I. The EPO dose (88 vs 85 U/kg/week,p = ns) was similar in the two groups.Our data showed that elderly patients with HPTHhave lower Hct and Hb levels than do youngerpatients on a similar EPO dose. We believethese patients will need a more aggressivetherapy with calcitriol.     

Iron homeostasis in relapsing steroid-sensitive nephrotic syndrome of childhood.

AIM: Urinary transferrin loss is a typical feature in relapse of the idiopathic nephrotic syndrome, however, the impact on serum iron homeostasis and hematological parameters has not been studied systematically so far. PATIENTS AND METHODS: Therefore, we investigated serum iron (Fe), erythropoietin (EPO), ferritin (FN), transferrin (TF), total iron-binding capacity (TEBK), transferrin saturation and the soluble transferrin receptor (sTFR) combined with hematological parameters (hemoglobin, MCV, MCH) in 42 children with relapsing, steroid-sensitive nephrotic syndrome (NS) in remission (RM, n = 26) and relapse (RL, n = 16), including 13 patients who were studied in both states. Thirty-three age-matched healthy children served as controls. RESULTS: Fe, TEBK and TF were significantly reduced in RL compared to RM in cross-sectional as well as in paired studies while ferritin, hematological parameters and EPO levels remained unchanged. A significant increase, however, of the soluble transferrin-receptor could be demonstrated in cross-sectional analysis comparing RL to RM and healthy controls (3568+/-713 mg/ml vs 2625+/-576 vs 2646+/-697; p < 0.001 respectively) as well as in paired analysis of 13 patients in RL and RM (p < 0.001). CONCLUSION: We conclude that transient transferrin and iron deficiency occurs in RL of INS but this seems to be counterbalanced by upregulation of the sTFR, a mechanism that might be important in preventing the development of iron deficiency anemia during the active nephrotic state.