Serum transferrin receptor concentration is not indicative of erythropoietic activity in chronic hemodialysis patients with poor response to recombinant human erythropoietin

BACKGROUND: Serum transferrin receptor (sTfR) is a transmembrane glycoprotein derived from erythroid precursors in the bone marrow. Its concentration provides a quantitative measure of total erythropoietic activity and an indication of functional iron deficiency. This study was conducted to investigate whether sTfR is a useful index of erythropoietic activity in chronic hemodialysis patients with poor response to maintenance recombinant human erythropoietin (rHuEPO) therapy. METHODS: Using an enzyme-linked immunosorbent assay, sTfR concentration was measured in 67 uremic patients who had been on hemodialysis for a mean of 42 months (3-242 months). rHuEPO was administered three times a week to keep the hematocrit above 30%. Hemoglobin, red blood cell indices, serum ferritin, serum total iron binding capacity and unsaturated iron binding capacity were determined. Of the 67 patients, 35 who responded favorably to rHuEPO with hematocrits above 30% were categorized as Group I and 32 who did not attain the target hematocrit were categorized as Group II. As a control group, 31 healthy subjects were also investigated. RESULTS: The serum iron, ferritin, transferrin iron saturation, dialysis efficiency and nutritional state were not different between groups of hemodialysis patients. The mean sTfR concentration was 2.1 +/- 0.6 micrograms/ml (range, 1.15-3.53 micrograms/ml) in Group I patients, compared with 1.9 +/- 0.9 micrograms/ml (range, 1.03-2.65 micrograms/ml) in Group II. The difference was not significant. In addition, the mean sTfR concentration of 1.8 +/- 0.4 micrograms/ml (range, 0.86-2.76 micrograms/ml) in the healthy controls was not significantly different from Groups I and II. CONCLUSIONS: sTfR concentration cannot be used to distinguish good from poor rHuEPO responders among chronic hemodialysis patients who have elevated serum ferritin (> 300 micrograms/l) and transferrin iron saturation (> 25%) during the course of maintenance rHuEPO therapy.     

Genetic predisposition to hypertension facilitates blood pressure elevation in hemodialysis patients treated with erythropoietin

PURPOSE: This study investigated the hypothesis that a genetic predisposition to hypertension is involved in the etiology of the elevation in blood pressure induced by human recombinant erythropoietin (rHuEPO). PATIENTS AND METHODS: Blood pressure changes after 10 weeks of treatment with rHuEPO were compared between 26 patients with a positive family history of hypertension and 27 with a negative family history. RESULTS: Mean blood pressure was significantly increased in patients with a positive family history of hypertension (+8.8 mm Hg, p < 0.001). In contrast, the change was not significant in those whose family history was negative (+1.8 mm Hg, not significant). The mean blood pressure of 14 of 26 patients with a positive family history of hypertension increased by more than 10%, whereas such an increase occurred in only 2 of 27 patients with a negative family history (p < 0.001). The two groups were similar in terms of the total dose of rHuEPO given, the degree to which their anemia improved, and their basal blood pressures. CONCLUSION: It appears that hemodialysis patients with a positive family history of hypertension are susceptible to developing hypertension during treatment with rHuEPO.     

Hemocompatibility in hemodialysis and erythropoietin therapy

Two studies designed to investigate the effect of recombinant human erythropoietin (rHuEPO) treatment of anemia in chronic dialysis patients on hemocompatibility were conducted. Study 1, whose main aim was to establish whether treatment with rHuEPO enhances coagulation activation during dialysis, included 15 patients before rHuEPO therapy at a mean hematocrit (HCT) of 22.3% and then during therapy at a HCT of 29.3%. The plasma concentrations of the thrombin-antithrombin III complex were not higher during rHuEPO therapy than before it when performing hemodialysis with a Cuprophan membrane. No significant difference was demonstrated either in the values of activated clotting times (Hemochron), thrombocyte or white blood cell counts (Coulter S+II), or in plasma C5a concentrations (ELISA) established during dialysis sessions before and during rHuEPO therapy. In Study 2, which focused primarily on the question of whether or not rHuEPO therapy increases thrombocyte activation during hemodialysis, 8 patients on chronic dialysis were examined both before therapy at a mean HCT value of 22.1% and during rHuEPO therapy at a HCT of 31.5%, invariably during dialysis with either a Cuprophan or polyacrylonitrile (AN69HF) membrane. The plasma concentrations of beta-thromboglobulin (ELISA) did not differ between the examinations made during rHuEPO and before rHuEPO therapy; however, statistically significant differences were found between dialysis sessions involving Cuprophan and AN69HF membranes. No significant difference between examination before and during rHuEPO was demonstrated in activated clotting time nor thrombocyte and white blood cell counts in this study either. The authors conclude that rHuEPO therapy does not enhance coagulation activation during hemodialysis, does not have an effect on thrombocyte activation, and does not influence complement activation and changes in white blood cell counts.     

Early and late effects of erythropoietin on glucose metabolism in maintenance hemodialysis patients

The effects of recombinant human erythropoietin (rHuEPO) on the glucose metabolism were evaluated by intravenous glucose tolerance test in 20 maintenance hemodialysis patients. In 8 cases the glucose tolerance tests were performed before and after a single intravenous injection of 50 IU/kg of rHuEPO and in 12 cases before and after 3 months of rHuEPO therapy at doses of 50 IU/kg three times/week and 2 weeks after rHuEPO withdrawal. For each test glucose, immunoreactive insulin (IRI) and C peptide (C-p) plasma values were measured, and glucose constant decay, whole IRI (area IRI) and C-p area C-p) production, insulinogenic index, and insulin resistance index were calculated. After 3 months of rHuEPO therapy, the glucose constant decay increased significantly, area IRI, area C-p, and insulin resistance index decreased significantly, and the insulinogenic index did not change. No correlations were found between changes in hemoglobin values and changes in glucose metabolism parameters. Acute rHuEPO administration and rHuEPO withdrawal had no effect on glucose metabolism, despite significant changes in plasma erythropoietin levels. Long-term rHuEPO therapy improves glucose metabolism in maintenance hemodialysis patients significantly, mainly by reduction of insulin resistance. Neither anemia correction nor a direct effect of rHuEPO on some metabolic steps seem to be responsible of these effects.     

The erythropoietin response to the anemia of thermal injury

Erythropoietin excretion was persistently increased following major thermal injury in 4 of 5 patients. A good correlation was found between erythropoietin excretion and red cell mass but not between erythropoietin excretion and hematocrit. In spite of the increased erythropoietin, erythropoiesis in these thermally injured patients was inadequate to compensate for erythrocyte deficits as judged by bone marrow morphology, reticulocyte counts, and transfusion requirements.     

Recombinant human erythropoietin (rhEPO) treatment potentiates growth hormone (GH) response to growth hormone releasing hormone (GHRH) stimulation in hemodialysis patients

On the basis of previously described effects of recombinant human erythropoietin (rhEPO) treatment on endocrine abnormalities present in uremia, we assessed the possible effect of treatment with rhEPO on growth hormone (GH) response to growth hormone releasing hormone (GHRH) in a group of uremic patients. Eight patients on maintenance hemodialysis for 12 to 228 months, not previously treated with rhEPO, were tested with 100 micrograms of GHRH i.v. in bolus before and after three months of rhEPO treatment (40 U/kg i.v. three times a week). Before treatment, the GH response to GHRH was characterized, in uremic patients, by remarkable differences in plasma GH values and in the pattern of response curve in single patients. The variability of GH response was not modified after rhEPO treatment; however, an overall potentiation of GH response with a significant increase of plasma GH (p = 0.017 at 15 min, p = 0.035 at 30 min after GHRH injection) was observed in the tests performed after treatment. rhEPO administration induced an evident improvement of anemia, blood hemoglobin concentration being 5.3-7.6 g/dl before and 9.1-11.3 g/dl after treatment; however a demonstrable correlation between the potentiation of GH response to GHRH and the increase of hemoglobin concentration was not observed.     

Role of magnetic resonance in hemodialysis patients with amyloid shoulder arthropathy]

Monoclonal antibodies (MAbs) were generated by immunizing mice with a truncated recombinant protein corresponding to the immunodominant region (residues 1-120) of hepatitis C virus (HCV) nucleocapsid protein. The specific recognition by either human sera or mouse monoclonal antibodies of overlapping peptides spanning the core region 1-120 as well as the comparison with epitopes described earlier allowed the fine mapping of HCV core. Within the region 1-120, the major antigenic domain could be restricted to the first 45 amino acids. Indeed, the peptide S42G (residues 2-45) allowed the detection of an anti-HCV core response by all anticore-positive human sera examined. According to their epitope localization, three groups of mouse MABs could be evidenced that were directed against different regions of core. Group II MAbs recognized a strictly linear epitope (QDVKF, residues 20-24), whereas group I MABs were directed against a conformational epitope mainly located at the amino acid residues (QIVGG, 29-33). The epitope of group III MABs was also conformational (PRGRRQPI, residues 58-65). These three epitopes appeared close but different from the three major human epitopes RKTKRNTN, VYLLPR, and GRTWAQPGYPWPLY (residues 7-17, 34-39, and 73-86, respectively). Group II MAB 7G12A8 and group I MAB 19D9D6 were used in a sandwich ELISA for the capture and the detection, respectively, of viral core antigen in sera of patients with chronic HCV infection. After treatment of sera with triton x 100 in acidic conditions, amounts of viral antigen as low as 20 pg/ml of sera could be detected.     

Role of cytokines in AIDS wasting

There is now a large literature implicating cytokines in the development of wasting and cachexia commonly observed in a variety of pathophysiologic conditions. In the acquired immunodeficiency syndrome (AIDS), cytokines elicited by primary and secondary infections seem to exert subtle and sustained effects on behavioral, hormonal, and metabolic axes, and their combined effects on appetite and metabolism have been postulated to drive wasting. However, correlations of increased blood levels of a particular cytokine with wasting in AIDS have not been consistent observations, perhaps because cytokines act principally as paracrine and autocrine hormones, as well as indirectly by activating other systems. A better understanding of the mechanisms underlying the catabolic effects of cytokines in clearly needed if more efficacious strategies are to be developed for the prevention and treatment of wasting in AIDS. In this review we first examine the interacting factors contributing to the AIDS wasting syndrome. We then analyze the complex and overlapping role of cytokines in the pathophysiology of this condition, and put forward a number of hypotheses to explain some of the most important features of this syndrome.     

Immune response and in vivo production of cytokines in patients with liver hydatidosis

Cytokines play an important role in the human immunological response, but the exact role of cytokines in the human immune response against parasites, especially against Echinococcus granulosus, remains unclear. IL-1, IL-2, IL-4 and tumour necrosis factor (TNF) levels in peripheral blood of 21 patients with liver hydatidosis were evaluated before surgical treatment, and the levels of IgA, IgM, IgG, IgE, specific IgE against E. granulosus, C3, C4 and DF complement fractions and CD20, CD3, CD4, CD8 and CD16 cell percentages were also determined, as was the relationship between these variables and cytokine levels. Data from hydatid patients were compared with data obtained from 21 healthy volunteers. Hydatid patients showed increases of IgG, IgE, IgEs and IL-2 (P < 0.01), and decreases of IL-1 and TNF levels (P < 0.001), but these variables (respectively) increased in patients showing cysts in the central area of the liver or with a wide opening of cysts in the biliary tract. The increase of IL-1, IL-2 and IL-4 showed a close relationship with the number, characteristics and above all the location of cysts within the liver itself. IgG and IL-4 levels and also IgG and IgE levels showed a significant correlation (P < 0.05).     

Recombinant human erythropoietin resistance in hemodialysis. Effects of paired filtration dialysis

A percentage of hemodialysis (HD) patients are resistant to recombinant human erythropoietin (rHuEPO), a phenomenon that occurs less frequently in patients dialyzed with biocompatible membranes (M) and in peritoneal dialysis. The authors evaluated the effects of paired filtration dialysis (PFD)--a dialysis technique based on the use of an emophan M in conjunction with a polysulphone M--on erythropoiesis in HD patients resistant to rHuEPO. Twelve HD patients with anemia resistant to long-term therapy with rHuEPO (200.24 U/kg body weight three times per week intravenously for 10.2 months) were studied. Patients had been treated for an average of 46.9 months with bicarbonate HD, using cuprophan M (Phase A) and, successively, for 12 months by PFD (Phase B). The following parameters were evaluated monthly: 1) hemoglobin and hematocrit values; 2) serum levels of erythropoietin (EPO); and 3) serum levels of interleukin (IL)-3, IL-6, IL-10, IL-1 beta, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma). At the end of Phase A and Phase B, patients underwent bone marrow biopsies to evaluate 1) bone marrow burst forming unit erythroid (BFU-E) and colony forming unit erythroid (CFU-E) proliferative capacity, and 2) bone marrow mononuclear cell EPO-receptor (EPO-R) number. During Phase B, there was a progressive rise in hematocrit and hemoglobin values, so that within the sixth month, the rHuEPO dose was reduced to 80 +/- 15 U/kg body weight three times per week. At the same time, an increase in serum IL-3, IL-6, and IL-10 levels was seen, whereas serum IL-1 beta, TNF-alpha, and IFN-gamma levels decreased. This was accompanied by a rise in BFU-E and CFU-E growth and in bone marrow mononuclear cell EPO-R number. During Phase B, after the dialysis session, serum EPO levels increased by about 30% in comparison with pre dialysis values, whereas during Phase A they decreased by about 14%. In HD patients, EPO resistance may caused either by absorption of rHuEPO to the cuprophan M, or an increased release of cytokines that inhibit erythropoiesis, such as IL-1 beta, TNF-alpha, and IFN-gamma, and to a decrease in stimulatory cytokines such as IL-3, IL-6, and IL-10. These negative phenomena are reversed by the use of biocompatible dialysis techniques such as PFD.     

Effects of zinc supplementation on the immune system and on antibody response to multivalent influenza vaccine in hemodialysis patients

BACKGROUND: It has been theorized that fetal myelomeningocele repair may reduce ongoing intrauterine injury and perhaps allow healing and regeneration of dysplastic neural tissue. We report on the postnatal imaging studies of the first 4 patients to have undergone intrauterine myelomeningocele repair at our institution. METHODS: Each of the 4 patients underwent postnatal sonographic and MRI. In addition, the postnatal ultrasounds of these 4 were compared to a group of retrospective controls. RESULTS: MRI scans of the 4 experimental subjects revealed no evidence of hindbrain herniation while other stigmata of the Chiari-II malformation persisted. In comparison to the retrospective controls this absence of herniation was distinctly unusual. CONCLUSION: Intrauterine myelomeningocele repair may reduce the degree of hindbrain herniation normally seen in patients with myelomeningocele. This raises the possibility that intrauterine repair may decrease the morbidity associated with the Chiari type-II malformation including brainstem dysfunction, hydrocephalus and syringomyelia.     

Murine splenic proliferative response to human recombinant erythropoietin along hypoxia

Hypoxia is the best physiological stress to disturb the erythropoietic steady state. The present study has been undertaken in the aim to analize the splenic erythropoietic proliferative response with different doses of recombinant human erythropoietin under hypoxic conditions along 18 days using the DNA synthesis assay. Normoxic splenic progenitors failed to show significative erythroid replication at 0 days. A clearly rh Epo response was noticed from 2 to 8 days of hypoxia. Splenic proliferation returned to basal pattern from 10 days to the end of the experience. The highest proliferative activity, 25 fold increase over control (p < 0.001), was found at 6 days from 62.5 to 250 mU/ml rh Epo. These results support suggestions that hypoxia induces a transiently erythroid splenic proliferative response changing its quantitative parameters in the Epo dose-response relationship during the physiological adaptation.     

Early prediction of response to recombinant human erythropoietin in patients with the anemia of renal failure by serum transferrin receptor and fibrinogen

Recombinant human erythropoietin (rHuEpo) has been shown to be effective in correcting the anemia of chronic renal failure, but the dose needed may be variable. The reason for this variation is not known, but several factors could be involved, such as iron deficiency, inflammation, aluminum intoxication, hyperparathyroidism, blood losses, or marrow dysfunction. Treatment with rHuEpo was given intravenously thrice weekly after hemodialysis to 64 consecutive unselected patients with the anemia of chronic renal failure. The starting dose was 50 U/kg/dose, which was increased to 75 and 100 U/kg/dose if no response was observed after 1 and 2 months of treatment. After a minimum follow-up of 6 months, response was evaluated as early (hematocrit [Hct] > or = 30% before 3 months) or late (Hct > or = 30% after 3 months) response, or failure (target Hct not attained). We examined the value of various laboratory parameters (baseline values and early changes) as predictors of response to rHuEpo. The best prediction by pretreatment parameters only was obtained with baseline serum transferrin receptor (TfR) (< or > or = 3,500 ng/mL) and fibrinogen (< or > or = 4 g/L): 100% response rate when both parameters were low, versus only 29% when they were both high, and versus 67% when one was low and the other high. When the 2-week TfR increment was greater than 20%, the response rate was 96%. When TfR increment was less than 20%, the response rate was 100% when baseline TfR and fibrinogen were low, 12% when fibrinogen was elevated, and 62% when fibrinogen was low but baseline TfR high. The predictive value of baseline TfR and fibrinogen and of the 2-week increment of TfR was confirmed by life table analysis and stepwise discriminant analysis. Major reasons for failure or late response were identified and included subclinical inflammation, iron deficiency, functional iron deficiency, marrow disorders, hemolysis, bleeding, and low Epo dose. We conclude that response to rHuEpo can be predicted early by pretreatment fibrinogen and TfR, together with early changes of TfR levels. These prognostic factors illustrate the importance of the early erythropoietic response, subclinical inflammation, and functional iron deficiency. Early recognition of a low probability of response in a given patient could help identify and correct specific causes of treatment failure to hasten clinical improvement and avoid prolonged ineffective use of an expensive medication.     

Response to recombinant human erythropoietin in patients with myelodysplastic syndromes

OBJECTIVES: The impact of a positive surgical margin in otherwise confined prostate cancer after radical prostatectomy remains unclear. We analyzed the outcome of a large number of patients with organ-confined prostate cancer according to the presence and anatomic site of margin positivity. METHODS: We evaluated 2712 prostatectomy patients with Stage pT2N0 cancer (ie, no evidence of extra-prostatic disease, seminal vesicle or regional node involvement) and no prior therapy who were treated by radical prostatectomy between 1987 and 1995 at Mayo Clinic. A total of 697 patients (26%) had positive margins. To assess the effect of margin status in the absence of treatment, 378 patients with postoperative adjuvant therapy were not considered for the study group: the final group consisted of 2334 patients. RESULTS: Overall, 253 (58%) tumors were positive at the apex and/or urethra, 85 (19%) at the prostate base, 11 (2.5%) at the anterior prostate, and 174 (40%) at the posterior prostate; 89 (20%) had at least two margins involved and 21 (8.3%) had more than two involved. The apex/urethra was the only positive anatomic site in 183 (42%). Five-year survival free of clinical recurrence or prostate-specific antigen (PSA) biochemical failure (postoperative serum PSA of 0.2 ng/mL or more) for patients with a single positive margin was 79% for apex or urethra, 78% for anterior/posterior, and 56% for prostate base. Five-year survival free of clinical recurrence or PSA (biochemical) failure was slightly higher for those with one versus two margin-positive regions (77% versus 68%, respectively). Multivariate analysis revealed that positive surgical margins were a significant predictor of clinical recurrence and PSA (biochemical) failure (relative risk [95% confidence interval]: 1.65 [1.24, 2.18]) after controlling for Gleason grade, preoperative PSA, and deoxyribonucleic acid (DNA) ploidy. The effect of margin positivity on recurrence at a specific anatomic site (versus negative margins or positive at a different anatomic site) revealed the prostate base to be the only significant anatomic site when adjusted for grade, PSA, and ploidy. Five-year survival free of the combined clinical or PSA failure end point for those with versus those without positive margins at the prostate base was 56% versus 85%, respectively (P < 0.0001). CONCLUSIONS: Positive surgical margins are a significant predictor of recurrence in Stage pT2N0 cancer, which is independent of grade, PSA, and DNA ploidy. The impact of positive margin status on recurrence-free survival appears to be anatomic and site-specific, with prostate base positivity significantly associated with poor outcome. The benefit of adjuvant therapy based on anatomic site-specific margin positivity remains to be tested in order to optimize recurrence-free survival.