Reduction in liver iron in hemodialysis patients with transfusional iron overload by deferoxamine mesylate

Four hemodialysis patients with transfusional iron overload were treated with three times weekly intravenous (IV) deferoxamine mesylate during the dialysis treatment. Using a gamma ray scattering technique, significant reductions in liver iron content were documented, with a mean follow-up of 20 months. Three of the four patients showed significant improvements in liver enzymes. This decrease in liver iron content could not be predicted by clinical parameters or serum ferritin. Therapy proved to be safe and effective, but follow-up requires monitoring of tissue iron by means other than standard laboratory tests.     

Intraperitoneal deferoxamine therapy for iron overload in children undergoing CAPD

We treated three children with renal failure and chronic iron overload with intraperitoneal deferoxamine therapy. Each child had an elevated serum ferritin level, a dense liver as measured by computerized tomography (Hounsfield Units) and one had dialysis related porphyria cutanea tarda. Deferoxamine therapy (10 to 17.5 mg/kg) was given in the overnight exchange for three to six months. Prior to therapy, iron was not detected in the dialysate; during the course of therapy, daily dialysate iron removal averaged 5652 micrograms, 2241 micrograms and 4028 micrograms in the three children. The serum ferritin level fell during the course of therapy in two children who were estimated to be in negative iron balance, and was unchanged in the third who was estimated to be in positive iron balance due to frequent transfusions. In 10 children with chronic renal failure, there was a linear correlation (r = 0.855; P less than 0.01) between the serum ferritin and the liver density, suggesting that an increased serum ferritin correlates with hepatic iron content. Interestingly, in each of the three children who received deferoxamine therapy, the liver density increased during therapy regardless of the estimated iron balance and the change in the serum ferritin level. We conclude that intraperitoneal deferoxamine therapy results in substantial iron losses in peritoneal dialysate, can result in negative iron balance but, in this study, did not result in lower liver iron content as measured by density on computerized tomography scan.     

去铁胺对输血相关性铁过载患者骨密度的影响

目的观察输血相关铁过载患者在使用去铁胺(DFO)降铁治疗后骨密度的变化,探讨去铁胺对铁过载骨质疏松患者辅助治疗的应用前景。方法回顾性研究22例输血相关铁过载患者临床资料,检测患者DFO降铁治疗前后的骨密度和血清生化指标。采用配对样本t检验、Wilcoxon非参数检验分析研究患者DFO降铁治疗前后骨密度以及血清生化指标的变化。结果进行DFO有效的铁螯合治疗后,患者血清铁蛋白(Fer)明显下降,由基线水平的2019.95±630.77 ng/m L降至843.61±91.01 ng/m L(P0.05);股骨颈和腰椎的骨密度明显增加,分别由基线水平的0.73±0.12 g/cm2、0.92±0.14 g/cm2增加至0.77±0.09 g/cm2、0.94±0.14 g/cm2(P0.05);骨量正常、骨量减少和骨质疏松患者分别由治疗前的4、12、6例变为治疗后的10、11、1例(P0.05)。结论 DFO降铁治疗可改善输血相关铁过载患者的低骨量状态。本研究为DFO可能用于伴有铁过载的骨质疏松症的辅助治疗提供了有意义的支撑。     

Kinetics and efficacy of deferoxamine in iron-overloaded hemodialysis patients

We evaluated the kinetics and efficacy of deferoxamine (DFO) therapy in iron-overloaded hemodialysis patients. Concentrations of DFO and its chelated product, feroxamine (Fx), were assessed following single-dose DFO administration in twelve patients, and during chronic therapy over one year's time in eight, similarly iron-overloaded dialysis patients. A functional assay which relies on measurements of iron and iron binding capacity for the determination of Fx and DFO, respectively, was corroborated with liquid chromatographic techniques. Half-life measurements were also corroborated with tracer doses of 14C-DFO and 59Fe-feroxamine. Intradialytic DFO half-life (2.3 +/- 1.1 h) was considerably less than interdialytic half-life (26 +/- 1 hr). Unbound DFO was found to persist throughout the interdialytic period. Calculation of the percent saturation of the DFO dose indicated that only 30% of a given dose is chelated. The amount of iron removed dialytically was approximately 13.1 +/- 2.7 mg per dialysis session. Chronic DFO administration was also shown to enhance gastrointestinal iron excretion threefold. However, ferritin levels decreased by only 25% after one year of thrice-weekly DFO therapy. We conclude that DFO therapy for iron-overloaded hemodialysis patients is optimized by its administration interdialytically, and results in slow removal of iron, via both dialytic and gastrointestinal routes.     

Serum ferritin as a guide for iron stores in chronic hemodialysis patients

The serum ferritin (SF) level was measured in 58 chronic hemodialysis (CHD) patients (46 living and 12 deceased subjects) and compared to bone marrow iron concentrations, cytological bone marrow iron stores (BMIS), and histological BMIS. In the 12 deceased subjects, liver iron concentrations, histological liver parenchymal, and Kupffer cell iron stores were also studied. The mean SF level of the whole group was 302 +/- 251 ng/ml (mean +/- SD). No close relationship was found between transferrin saturation and cytological BMIS. A high correlation was found between SF level and cytological BMIS (Spearman rank rs = 0.74). In the deceased CHD patients a close correlation was observed between histological parenchymal liver iron stores and histological Kupffer cell iron stores, but not between liver and bone marrow iron stores. A good correlation was found between SF levels and liver iron concentrations. It is concluded that in CHD patients SF levels are higher than in healthy controls, even in the absence of iron therapy (except in the form of blood transfusions); in some of these patients iron is disproportionately stored in the bone marrow and the liver. Although the level of BMIS cannot be estimated unequivocally from an SF measurement in every CHD patient, SF levels provide useful estimates of BMIS.     

Low dose intravenous ascorbic acid for erythropoietin-hyporesponsive anemia in diabetic hemodialysis patients with iron overload

BACKGROUND: Recent report demonstrates that inadequate iron mobilization and defective iron utilization may cause recombinant erythropoieitin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. The effect of intravenous ascorbic acid (IVAA) in HD patients selected on the basis of iron overload and EPO resistance also has been proven. However, it is uncertain whether IVAA still works in diabetic ESRD patients with hyperferritinemia. Therefore, the aim of this study focusing on diabetic ESRD patients was to analyze the potential effect of low dose IVAA on improvement of anemia and erythropoiesis-related parameters when compared with control period. PATIENTS AND METHOD: This study consisted of 22 chronic hemodialysis patients with type II diabetes in a single dialysis unit. In studies of this type, all eligible patients are followed up, but the primary comparison is still between different sequentially treatment including control period and post-IVAA period in same patients. IVAA patients received ascorbic acid, 100 mg each administered intravenously three times per week for eight weeks of treatment and four months of post-treatment follow-up. RESULTS: The demographic characteristics of 22 diabetic uremic patients show that mean age is 63.6 +/- 10.2 years old. The ratio of sex (M/F) = 10/12. Mean duration of HD is 46.7 +/- 33.2 months. As for the urea kinetic study between these two periods including KT/V, nPCR, and URR, there is no significantly different. As for anemia-related parameters, Hb and Hct increased significantly in post-IVAA period after 3 months compared with control period, while MCV did not increase significantly. Serum ferritin significantly decreased at study completion. The same situation is for iron. As for TS, it significantly increased at one month and further markedly increased at subsequent three months. CONCLUSION: This study has demonstrated that short-term low dose IVAA therapy can facilitate iron release from reticuloendothelial system but also increase iron utilization in diabetic hemodialysis patients with iron overload. Therefore, IVAA is a potential adjuvant therapy to treat erythropoeitin-hyporesponsive anemia in iron-overloaded patients.     

Serum paraoxonase activity in uremic predialysis and hemodialysis patients

BACKGROUND: Paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated enzyme and has been shown to reduce the susceptibility of low-density lipoprotein (LDL) to lipid peroxidation. This study aimed to investigate the activity and phenotype distribution of serum paraoxonase in uremic patients, and to evaluate the correlations of uremia-associated substances (urea, creatinine (Cr) and uric acid) with paraoxonase activity. METHODS: Twenty-eight patients with chronic renal failure (CRF), 44 patients with CRF undergoing hemodialysis (HD) and 26 healthy controls were included in this study. Paraoxon or phenylacetate was used as a substrate for measuring paraoxonase and arylesterase activity, respectively. The double substrate method was used to assign phenotypes. Serum lipid parameters were determined by routine laboratory methods. RESULTS: Paraoxonase activity, HDL-cholesterol and apolipoprotein (apo) AI levels were found to be significantly lower in HD patients than in controls. However, HDL-standardized paraoxonase activity (PON activity/HDL) was not different in the HD patients compared to controls. Arylesterase activity was significantly lower in both CRF and HD patients than in controls. Paraoxonase phenotype distribution was not different among the groups according to the double substrate method. Serum paraoxonase and arylesterase activities correlated inversely with serum urea and Cr levels. CONCLUSION: Patients on long-term HD have reduced paraoxonase/arylesterase activities and this could be related to reduced HDL-cholesterol and apo AI levels, as well as increased urea and Cr levels in uremia.     

Recombinant human erythropoietin and phlebotomy in the treatment of iron overload in chronic hemodialysis patients

Five long-term hemodialysis patients with clinical iron overload were treated with 300 U/kg of recombinant human erythropoietin (rHuEPO) intravenously (IV) after each hemodialysis. The patients were phlebotomized after each hemodialysis at any time the predialysis hematocrit was 35% or greater. Over a period of 1 year, the average phlebotomy rate varied from 0.5 to 1.1 U/wk with a mean phlebotomy rate of 45.8 +/- 5.6 U/yr (range, 27 to 57 U). The mean serum ferritin decreased from 8,412 +/- 1,599 micrograms/L (ng/mL) to 3,007 +/- 1,129 micrograms/L (ng/mL), and the mean iron removal over this period was 9.5 g. Liver iron deposition, as measured by density on computed tomographic (CT) scan, improved, while skin color lightened significantly. Patients tolerated phlebotomy with no major symptoms or complications and exhibited no change in the hemogram or serum chemistries. In patients with severe iron overload, changes in serum ferritin with erythropoietin treatment alone may not reflect true change in iron burden. Use of high-dose erythropoietin and phlebotomy is an effective and safe (at least for 1 year) method of reducing iron overload in long-term hemodialysis patients.     

Progressive vascular calcification with necrosis of extremities in hemodialysis patients: a possible role of iron overload

Progressive vascular calcification with ischemia and gangrene of the extremities occurs rarely in uremic patients, patients undergoing maintenance dialysis, and following renal transplantation. In this paper we present two additional patients on chronic hemodialysis who developed this syndrome in association with severe secondary hyperparathyroidism. Fulminant gangrene led to the death of the first patient, while in the second, multiple amputations had to be performed after parathyroidectomy. In both patients, evidence of iron overload due to multiple blood transfusions was present and iron was histologically demonstrated in a calcification area in one case. The possibility of iron overload as a "challenger" for systemic calciphylaxis is discussed.     

Risk of iron overload and 'hemochromatosis allele(s)' in patients on maintenance hemodialysis

In the present study, we have evaluated the relationship between serum ferritin (SF) levels, 'hemochromatosis allele(s)', blood transfusions and iron parenteral administration in 69 hemodialysis patients. We demonstrated significantly higher SF levels in patients with hemochromatosis allele(s) (HA+) than in patients without hemochromatosis alleles (HA-). In addition, HA+ patients who had received blood transfusions up to 15 months prior to the study had SF levels even higher than those without blood transfusions. On the other hand, HA- patients had normal levels of SF, independent of blood transfusions. After intravenous administration of 1 g iron saccharate, SF levels were significantly higher only in HA+ transfused patients. In conclusion, our study demonstrated that HA+ patients are at a higher risk of iron overload and therefore the use of transfusional and/or parenteral iron should be strictly limited.     

持续性血液透析患者铁代谢与贫血状况的研究

目的 观察维持性血液透析(maintenance hemodialysis,MHD)患者铁过载的相关情况及其与贫血的相关性.方法 采用单中心、回顾性临床研究.选择2014年6月至2014年12月本院维持血液透析患者120例,按SF水平分为三组.A组(SF≤500 mg/L,n=60),B组(500 mg/L＜ SF≤1000 mg/L,n =35)和C组(SF＞ 1000 mg/L,n =25).调查患者的促红细胞生成素的用量、静脉补铁剂量、血红蛋白的变化、尿素氮、肌酐、全段甲状旁腺激素以及铁调素的水平.结果 C组患者的静脉铁补充剂量、输血量均大于A、B两组(P＜0.05),A组血红蛋白变化量大于B、C两组(P＜0.05),C组铁调素高于A、B两组(P＜0.05).结论 慢性肾衰竭维持血液透析的患者在SF≤500 mg/L,静脉补铁能有效地改善贫血,如补铁过量;SF＞ 1000 mg/L并不能显著的改善贫血及表现出铁代谢紊乱.     

Iron overload and mobilization in long-term hemodialysis patients

Iron overload from repeated transfusions of RBCs in long-term hemodialysis patients is a problem of increasing clinical significance. We report on the prevalence of and diagnostic criteria for identification of hemodialysis patients with iron overload. In 150 unselected hemodialysis patients, 62 (41%) had ferritin levels greater than 2,000 ng/mL (normal = 10 to 360 ng/mL). In 16 of these patients, accurate transfusion histories were obtained and ferritin levels correlated with calculated transfusional iron burden (r = 0.553, P less than .05). These patients could be divided into two distinct groups on the basis of their response to a single dose (2 g, IV) of deferoxamine: "high" responders had twice the level of feroxamine (the chelated product of deferoxamine and iron) of the "low" responders (P less than .001). High responders also had significantly higher prevalence of the "hemochromatosis" alleles A3, B7, and B14 than a large group of dialysis patients awaiting transplantation (71% v 37%, P less than .001). In two patients with iron overload and clinically significant bone disease, bone histology revealed prominent iron staining at the calcification front. We conclude that transfusional iron overload is a significant clinical problem in long-term hemodialysis patients, that may also be associated with bone pathology.     

Cardiac transplantation in patients with iron overload cardiomyopathy.

A review of the published world experience with heart transplantation for iron overload cardiomyopathy (IOC) between 1967 and 2003 as well as review of unpublished cases from the database of the United Network for Organ Sharing since 1992, identified a total of 16 patients (14 men and 2 women). Mean age was 31 years (range, 14-63 years). IOC etiology was hemochromatosis in 11 patients (69%), thalassemia major in 4 (25%), and Diamond-Blackfan anemia in 1 (6%). The 30-day mortality was 12%. Three patients (19%) died within 1 year of the transplant, all of infectious complications. An additional patient died at 7.14 years (unknown cause). The actuarial Kaplan-Meier 1-, 3-, and 5-year survival rates were 81% for all 3 time intervals. The actuarial 10-year survival was 41%.     

Septicemia due to Yersinia enterocolitica in a hemodialyzed, iron-depleted patient receiving omeprazole and oral iron supplementation.

Septicemia occurred in a long-term hemodialysis patient on oral iron supplementation who had been treated for esophageal ulcer by omeprazole, an ulcer-healing drug. Yersinia enterocolitica serotype 0:3 was recovered from blood cultures. A raised intraintestinal pH and an increased intraluminal iron load may have been contributing factors for the enhanced proliferation and generalized infection of Y enterocolitica.     

Efficacy of hepatic computed tomography to detect iron overload in chronic hemodialysis

The diagnostic efficacy of hepatic computed tomography density (HCTD) in comparison with serum ferritin for the detection of iron overload was investigated in uremic patients on maintenance hemodialysis (HD) and in patients with idiopathic hemochromatosis (IHC). Ten IHC patients, 38 HD patients and 40 healthy subjects underwent the CT scanning of the liver and determination of percent saturation of transferrin, serum ferritin concentration and HLA typing. Liver iron content was determined by histochemical grading and direct measurement of liver iron concentration either in IHC patients or in HD patients. Nineteen HD patients were considered to have iron overload on the basis of liver iron concentration exceeding 3.6 mumol/100 mg dry weight. The mean +/- SD values of HCTD in healthy subjects, IHC patients, HD patients with iron overload and without iron overload were 60.2 +/- 5.6, 79 +/- 5.6, 71.4 +/- 3.6, 58 +/- 3.8 Hounsfield units, respectively. HCTD showed positive correlations with liver iron concentration and serum ferritin either in IHC patients or in HD patients. The analysis of the diagnostic efficacy of HCTD in comparison with serum ferritin for the detection of excessive hepatic iron in HD patients demonstrated that HCTD had higher sensitivity, specificity, positive and negative predictive values. Cut-off points were arbitrarily fixed to 66 Hounsfield units for HCTD, 400 micrograms/liter for serum ferritin and 3.6 mumol/100 mg dry weight for liver iron concentration. Seventeen HD patients who possessed the histocompatibility antigens associated with IHC, namely HLA-A3 and/or HLA-B7 and/or HLA-B14, had liver iron concentration, serum ferritin and HCTD values higher than those of the HD patients without these "hemochromatosis alleles".(ABSTRACT TRUNCATED AT 250 WORDS)     

Improvement of anemia with deferoxamine in hemodialysis patients with aluminum-induced bone disease

As microcytic anemia is a feature of aluminium intoxication, we prospectively studied the hematologic effects of deferoxamine in 10 hemodialysis patients with aluminum-induced bone disease. Comparing the mean monthly results of a 4 month period before and during deferoxamine therapy, we observed an important decrease of the transfusion needs (alpha less than 0.025) and an increase of hematocrit (p less than 0.02), hemoglobin (p less than 0.02), MCV (p less than 0.02) and MCH (p less than 0.05); the number of red blood cells remained unchanged. Our results show that deferoxamine treatment of dialysis patients with aluminum bone disease can markedly improve their anemia, even in the absence of recent aggravation, microcytosis and hypochromia. They also suggest that aluminum could participate in the anemia of dialysis patients even if it is normocytic.