Iron overload in kidney transplants: prospective analysis of biochemical and genetic markers

BACKGROUND: The prevalence of iron overload and the influence of mutations in the HFE and TRF2 gene on biochemical markers of iron overload among renal transplant patients is unknown. METHODS: Serum iron, ferritin, transferrin saturation (TSAT), and liver function parameters were analyzed in a cohort of 438 renal transplants. In patients with iron overload, the time course of biochemical markers of iron status as well as the influence of iron loading mutations was investigated during a time period of 5 years. RESULTS: Of 438 renal transplant patients 41 (9.4%) presented with an iron loading phenotype (TSAT above 40% and/or ferritin above 800 ng/mL). Mutations in the HFE gene were present in 12 of 33 (36.3%) patients with iron overload. Among these one patient was homozygous for HFE C282Y, and two patients were compound heterozygous for HFE C282Y/H63D. No individual tested positive for nine other mutations in HFE as well as theTRF2 Y250X mutation. Over time we observed a decrease of mean iron and ferritin levels, and of mean TSAT in our study sample. In patients with mutations in HFE this decrease was less pronounced as compared to patients without mutations. We found an independent positive association between the presence of mutations in HFE and serum alanine-aminotransferase levels at follow-up (P= 0.003). CONCLUSION: Our study demonstrates that iron overload is frequently present in renal transplant patients and shows a continuous decrease over time. This decrease is possibly impaired by the HFE C282Y and HFE H63D mutations. Furthermore, mutations in HFE may influence liver function as reflected by increased alanine-aminotransferase concentrations.     

Iron deficiency anemia and iron losses after renal transplantation

Iron deficiency contributes to anemia after transplantation. The magnitude of iron loss from blood loss in the peri-transplantation period has not been quantified. We prospectively estimated phlebotomy and surgical losses over the first 12-weeks following transplantation in 39 consecutive renal transplant recipients on hemodialysis (HD), peritoneal dialysis (PD), or chronic kidney disease (CKD). At transplant, ferritin levels were <200 ng/ml in 51% of the patients, and iron saturation was ≤20% in 44%. CKD patients more commonly had ferritin levels <200 ng/ml than either HD or PD patients (100% vs. 21% vs. 67%, P  < 0.0002, respectively). Blood loss was similar among HD, PD and CKD patients (833 ± 194 vs. 861 ± 324 vs. 755 ± 79 ml respectively, P  = NS), and no difference between deceased and living donor transplant recipients (881 ± 291 vs. 788 ± 162 ml, P  = 0.33). Based on baseline hemoglobin (Hgb) of 11.8 g/dl, we estimated that an additional 330 mg of iron was needed to normalize hemoglobin to 13 g/dl, and 605 mg to increase hemoglobin to 14 g/dl. Blood and iron losses over the first 12 weeks post-transplant are substantial and may warrant early administration of intravenous iron.     

Comparison of intravenous ascorbic acid versus intravenous iron for functional iron deficiency in hemodialysis patients

The effect of intravenous ascorbic acid was compared with that of intravenous iron in the treatment of functional iron deficiency, as defined as serum ferritin levels over 300 ng/ml and serum iron levels below 50 microg/dl, in patients on chronic hemodialysis. Thirteen patients on chronic hemodialysis with functional iron deficiency received intravenous injections of ascorbic acid, 100 mg, three times a week, after hemodialysis. The therapy was continued until serum ferritin decreased to below 300 ng/ml (3 months at the maximum). The iron and control group were composed of patients who had serum iron levels below 50 microg/dl within 3 months after serum ferritin rose to over 300 ng/ml. Seven patients with the iron group received more than a total of 10 intravenous injections of saccharated ferric oxide (40 mg/dose) after hemodialysis, and seven patients with the control group received no iron preparation during the 3 months. In the ascorbic acid group, while hemoglobin did not change from 10.9 +/- 0.5 g/dl (mean +/- SE) during the three-month period, serum iron increased significantly from 37 +/- 4 microg/dl to 49 +/- 4 microg/dl after one month (p<0.01), and remained elevated until the end of the three-month period. Serum ferritin decreased significantly from 607 +/- 118 ng/ml to 354 +/- 30 ng/ml after 3 months (p<0.01). In the iron group, hemoglobin and serum iron increased significantly from the respective pre-treatment levels during the 2-month period, and serum ferritin rose significantly after 3 months. In the control group, hemoglobin, serum iron and ferritin levels decreased significantly from the respective pre-treatment levels during the 3 months. The recombinant erythropoietin dose remained stable for three months in the ascorbic acid, iron, and control groups, respectively. These results suggest that in hemodialysis patients with a functional iron deficiency, treatment with intravenous ascorbic acid can prevent iron overload due to treatment with intravenous iron, and provide a useful adjuvant means of maintaining hemoglobin and serum iron levels.     

Anemia and iron deficiencies among long-term renal transplant recipients

Iron deficiency anemia after renal transplantation has not been systematically investigated. The prevalence of anemia and the indicators of iron deficiency among 438 renal transplant recipients were examined. Anemia was present in 39.7% of the patients. The prevalence of iron deficiencies, as indicated by a percentage of hypochromic red blood cells (HRBC) of >or=2.5%, was 20.1%. The majority of severely anemic patients exhibited HRBC values in the upper quartile. Positive associations of hemoglobin levels with creatinine clearance, serum transferrin levels, male gender, transferrin saturation (TSAT), polycystic kidney disease, and age were observed. Negative associations with erythropoietin therapy, use of azathioprine, serum ferritin levels, and body mass index were observed. The risk for anemia was closely related to the highest quartile of HRBC percentages (odds ratio, 2.35; 95% confidence interval, 1.48 to 3.75; P = 0.00029), whereas ferritin levels and TSAT conferred no risk for anemia. Therefore, assessment of the HRBC proportion is superior to decreased ferritin and decreased TSAT measurements for the diagnosis of iron deficiencies among renal transplant recipients.     

Time-dependent associations between iron and mortality in hemodialysis patients

The independent association between the indices of iron stores or administered intravenous iron, both of which vary over time, and survival in patients who are on maintenance hemodialysis (MHD) is not clear. It was hypothesized that the observed associations between moderately high levels of three iron markers (serum ferritin, iron, and iron saturation ratio) or administered intravenous iron and all-cause and cardiovascular death is due to the time-varying confounding effect of malnutrition-inflammation-cachexia syndrome (MICS). Time-dependent Cox regression models were examined using prospectively collected data of the 2-yr (July 2001 to June 2003) historical cohort of 58,058 MHD patients from virtually all DaVita dialysis clinics in the United States. After time-dependent and multivariate adjustment for case mix, administered intravenous iron and erythropoietin doses, and available surrogates of MICS, serum ferritin levels between 200 and 1200 ng/ml (reference 100 to 199 ng/ml), serum iron levels between 60 and 120 microg/ml (reference 50 to 59 microg/ml), and iron saturation ratio between 30 and 50% (reference 45 to 50%) were associated with the lowest all-cause and cardiovascular death risks. Compared with those who did not receive intravenous iron, administered intravenous iron up to 400 mg/mo was associated with improved survival, whereas doses >400 mg/mo tended to be associated with higher death rates. The association between serum ferritin levels >800 ng/ml and mortality in MHD patients seems to be due mostly to the confounding effects of MICS. For ascertaining whether the observed associations between moderate doses of administered intravenous iron and improved survival are causal or due to selection bias by indication, clinical trials are warranted.     

Anemia treatment with erythropoietin in pregnant renal recipients

Pregnancies in renal transplant patients are considered to be high risk. Anemia is one of the major complications of pregnancy occurring among 65% to 85% of cases in this setting, especially since these patients carry additional risk factors. Herein we have presented five renal transplant recipients who were women who were treated with human recombinant erythropoietin due to severe anemia that developed during pregnancy. Hemoglobin levels below 9 g/dL after 3 weeks of oral iron administration were assumed to be qualifying criteria for erythropoietin treatment. No complication was observed to be associated with the treatment. Two of the five patients required blood transfusions despite erythropoietin administration. Two cases delivered small for gestational fetus age. Erythropoietin therapy in pregnant kidney transplant recipients should be considered to be a safe method to reduce the need for blood transfusions.     

Iron metabolism in kidney allograft recipients: still a mystery?

Introduction

All living organisms have evolved sophisticated mechanisms to maintain appropriate iron levels in their cells and within their body. Recently our understanding of iron metabolism has dramatically increased. Overt labile plasma iron (LPI) represents a component of non-transferrin-bound iron (NTBI) that is both redox active and chelatable, capable of permeating into organs and inducing tissue iron overload. LPI measures the iron-specific capacity of a given sample to produce reactive oxygen species. We studied NTBI correlations with markers of iron status and inflammation in prevalent kidney allograft recipients.

Methods

Complete blood count, urea, creatinine, serum lipids, fasting glucose, ferritin, serum iron, and total iron-binding capacity (TIBC) were studied by standard laboratory method in the hospital central laboratory. NTBI was assessed by FeROS eLPI kit by Aferrix Ltd (Tel Aviv, Israel). A test result of 0.6 U of LPI or more indicated a potential for iron-mediated production of reactive oxygen species in the sample.

Results

In kidney transplant recipients NTBI was correlated with TIBC (r = .46, P < .001) and ferritin (r = .31, P < .05), with tendencies to correlate with C-reactive protein. Patients with LPI units ≥ 0.6 showed higher serum iron (P < .05), TIBC (P < .05), ferritin (P < .001) and mean corpuscular volume. High ferritin values together with elevated NTBI content were observed among patients undergoing multiple transfusions before and/or after transplantation.

Conclusions

Elevated NTBI as well as ferritin levels in kidney transplant patients may be due to disturbed iron metabolism, since the human body has no possibility to remove an iron excess. NTBI could be responsible for excessive synthesis of reactive oxygen species. Therefore, it may be linked to complications such as atherosclerosis, which is frequently encountered among this population.     

Diagnosis and treatment of iron overload in paediatric patients on chronic haemodialysis

In this study the incidence and contributing factors of iron overload in paediatric patients treated with intermittent haemodialysis were evaluated. Particular attention was given to the diagnostic value of serum ferritin in the assessment of body iron stores in patients with hepatocellular damage. The results of treatment of secondary haemosiderosis with desferrioxamine (DFO) are reported. Serum ferritin levels were measured in 18 children and adolescents undergoing long-term haemodialysis; 8 of these had biochemical evidence of hepatocellular damage. In all patients a good correlation was found between serum ferritin levels and the amount of iron stored in the reticuloendothelial system. Six patients developed iron overload. Patients with secondary haemosiderosis were younger at the start of haemodialysis and received significantly more blood. Although not significant, more patients with haemochromatosis-associated alleles and bilateral nephrectomy had iron overload, and the duration of dialysis was obviously longer for overloaded patients (40 months versus 26 months). The patients with iron overload were treated with DFO. The data from all patients showed that DFO was ineffective when administered at a dose of 25 mg/kg during dialysis and that in individual patients changes in serum ferritin correlated with changes in the amount of blood transfusions administered.     

Association between serum ferritin and measures of inflammation, nutrition and iron in haemodialysis patients.

BACKGROUND: Serum ferritin is a frequently used marker of iron status in dialysis patients. Iron administration is to be withheld for ferritin values >800 ng/ml according to K/DOQI guidelines. We hypothesized that such non-iron-related factors as elements of the malnutrition-inflammation complex syndrome (MICS) may increase serum ferritin concentration independently of iron status. METHODS: We studied 82 prevalent maintenance haemodialysis (MHD) patients (including 43 men), aged 55.7 +/- 15.3 years. The inflammatory and nutritional status was evaluated by serum C-reactive protein (CRP), Subjective Global Assessment (SGA) and its newer, fully quantitative versions, i.e. Dialysis Malnutrition Score (DMS) and Malnutrition-Inflammation Score (MIS). RESULTS: All but six patients had been on maintenance doses of intravenous iron dextran (between 100 and 200 mg/month) during the 10 weeks prior to the measurements. Serum ferritin levels were increased across SGA categories: (ANOVA P-value 0.03). Both unadjusted and multivariate adjusted correlation coefficients (r) for serum ferritin and CRP vs pertinent values were statistically significant for DMS and MIS and some other measures of nutritional status and iron indices. After deleting 10 MHD patients with either iron deficiency (ferritin <200 ng/ml) or iron overload (ferritin >2000 ng/ml), in the remaining 72 MHD patients both bivariate and multivariate correlations were much stronger and statistically significant (r = -0.33 and -0.29, respectively, P < 0.01). A multivariate model showed simultaneous, significant correlations between serum ferritin and both markers of inflammation and iron status independent of each other. After dividing the 72 MHD patients into two groups of serum ferritin based on a K/DOQI recommended serum ferritin cut-off of 800 ng/ml, the MIS and logarithm of serum CRP were significantly higher in the higher ferritin group. CONCLUSIONS: Serum ferritin values in the range of 200-2000 ng/ml may be increased due to non-iron-related factors including elements of MICS.     

Anemia in Heart and Kidney Allograft Recipients: Is There a Role for Hepcidin?

The production by hepatocytes of hepcidin, a small defensin-like peptide, is modulated in response to anemia, hypoxia, or inflammation. We studied hepcidin as a marker of iron status (serum iron, ferritin, and soluble receptor of transferrin [sTfR], and as a marker of inflammation among 170 prevalent kidney transplantation (KT) patients and 168 prevalent orthotopic heart transplant (OHT) patients. In addition, we assessed the prevalence of anemia and its relation to measurements of hepcidin, sTfR, and high-sensitivity C-reactive protein, using commercially available enzyme-linked immunosorbent assay (ELISA) kits. Prevalence of anemia was 37% in KT patients and 34% in OHT patients according to the World Health Organisation (WHO) definition. Anemic KT patients displayed significantly higher values of serum creatinine, hepcidin, hsCRP, ferritin, and proteinuria associated with greater use of mTOR and significantly lower CSA therapy. The hemoglobin and estimated glomerular filtration rate (eGFR). Upon multiple regression analysis eGFR, ferritin, and hsCRP independently predicted hepcidin levels, explaining 78% of the variation in hepcidin. Anemic OHT patients showed significantly lower GFR, red blood cell (RBC), and hemoglobin values and significantly higher creatinine and NT-proBNP content. Upon multiple regression analysis the predictors of serum hepcidin were eGFR and ferritin, which explained 68% of the variation in hepcidin. The prevalence of anemia is relatively high and not adequately treated (mainly due to reimbursement regulations) among heart and kidney allograft recipients. In conclusion, elevated hepcidin levels in heart and kidney transplant recipients suggest subclinical inflammation and impaired kidney function.     

Iron Overload: Predictor of Adverse Outcome in Hematopoietic Stem Cell Transplantation

Introduction

Iron overload is an important problem in candidates for and survivors of hematopoietic stem cell transplantation (HSCT), and affects long-term outcome and survival. The objective of the present study was to determine the effect of iron overload on early toxic or infectious complications and survival.

Patients and Methods

We retrospectively reviewed the medical records for 250 adult patients (162 men and 88 women; median [range] age, 34 [16-71] years who underwent HSCT between September 2003 and August 2008. The HSCT grafts were autologous in 102 patients, and allogeneic in 148.

Results

Follow-up was 315 (1-1809) days. Mean (SD) pre-HSCT serum ferritin concentration was 1402.6 (5016.2) ng/mL in the entire group, 647.6 (1204.3 ng/mL in autologous recipients, and 1410.6 (2410.4) ng/mL in allogeneic recipients. Twenty-eight autologous graft recipients (27.4%) and 102 allogeneic recipients (68.9%) demonstrated serum ferritin concentrations of 500 ng/mL or greater, and were classified as the high-ferritin group. High ferritin concentrations were significantly associated with toxic or infectious complications including mucositis, fungal infections, pneumonia, and sinusoidal obstruction syndrome in the early post-HSCT setting. A significant effect of pre-HSCT ferritin concentration on overall survival and transplant-related mortality was observed. The effect of pre-HSCT ferritin on survival was independent of the comorbidity index at Cox regression analysis. In the entire study population, the probability of survival was significantly lower when ferritin concentration was greater than 500 ng/mL.

Conclusion

Transplant-related mortality has decreased substantially with the development of supportive treatments. Pretransplantation risk assessment and risk-adapted strategies such as decreasing iron overload might further improve transplant-related complications.     

Serum ferritin levels after renal transplantation: a prospective study

A prospective study was made of the evolution of serum ferritin levels in 112 renal transplant recipients with good graft function. The rise in hemoglobin value is accompanied by a decrease in basal serum ferritin levels which are lowest at the sixth month: 54.9 (2-1,516) vs. 109.6 (21-4,420) micrograms/l, p less than 0.001 (Xg and range). After this time, ferritin values increase, although they do not reach basal levels. Evolution after transplantation is mainly determined by the previous state of iron stores at the time of transplantation. While in the patients with high basal serum ferritin values these gradually decreased during the follow-up period, patients with low basal serum ferritin levels tend to replenish their iron stores after renal transplantation. These differences disappear at the third year when serum ferritin values are similar in all groups. An association between persistence of posttransplant anemia and low serum ferritin levels is observed. This event is not clinically relevant as anemia disappears in almost all cases and dietary iron is enough to normalize serum ferritin levels.     

Issues related to iron replacement in dialyzed patients

Correction of renal anaemia by erythropoiesis stimulating agents (ESA) had reduced blood transfusion needs and iron overload risk and nowadays most of end-stage renal disease patients treated with dialysis requires i.v. iron supplementation to optimize the action of ESAs. Recommended targets for iron therapy are serum ferritin > 100 microg/l and hypochromic red cells percentage (HRC) < 10 (or transferrin saturation coefficient [TSAT] > 20% or reticulocyte Hb content [CHr] > 29 pg/cell). If i.v. administration is strongly recommended for all dialysis patients, controversies remain for the mode and rhythm of administration. Follow-up should be done every 1 to 3 months with measurement of serum ferritin in order to keep its level < 500 to 800 microg/l. Potential toxicity of chronic exposure to i.v. iron concerns tissue accumulation, consequences of pro-oxidant effects, cardiovascular damage and increased risk of infection but no clinical data unequivocally confirm that iron overload from parenteral iron contributes to all cause morbidity and mortality. In conclusion, i.v. iron should be used to optimize ESA action and could be used safety if dosage is < or = 100 mg/week and serum ferritin < 500 a 800 microg/l.     

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.     

Serum Hepcidin Level Correlates With Hyperlipidemia Status in Patients Following Allograft Renal Transplantation

Hepcidin is synthesized and secreted by liver cells and has been reported as one of the hormone molecules that regulates iron homeostasis. To determine whether serum level of hepcidin can be used as a biomarker for the evaluation of chronic inflammatory status, iron level and renal function in patients following allograft renal transplantation, serum levels of hepcidin, interleukin (IL)-6, ferritin, serum iron, and renal functions were measured. Sixty patients were included in the current study and were further separated into groups with or without hyperlipidemia. We found that allogeneic kidney transplant recipients with hyperlipidemia have significantly increased serum levels of hepcidin, IL-6, and ferritin. The increased serum hepcidin is positively correlated with serum IL-6 and ferritin as analyzed by single-factor correlation analysis. Multivariant correlation analysis in all specimens further demonstrated that serum hepcidin negatively correlated with glomerular filtration rate, and positively correlated with serum total cholesterol, triglycerides, serum ferritin, and IL-6. Our study demonstrated that serum level of hepcidin after allogeneic kidney transplantation not only reflects the status of chronic inflammation but can also indicate changes in renal function. Thus, hepcidin has the potential to be used as a promising marker for the detection and monitoring of the status of chronic inflammation, hyperlipidemia, and renal function in patients following allograft renal transplantation.     

Effect of repeated intravenous iron administration in haemodialysis patients on serum 8-hydroxy-2'-deoxyguanosine levels.

BACKGROUND: Iron supplementation is a mainstay for management of renal anaemia in patients receiving haemodialysis (HD). Although it is well known that a single intravenous iron (IVIR) administration transiently enhances oxidative stress in HD patients, the consequence of repeated IVIR administration is still unknown. This study aims to clarify the time course of changes in serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA oxidative injury, during a period of repeated IVIR administration in HD patients. METHODS: Twenty-seven patients (62+/-14 years and 23 males) on long-term HD participated in this study. All patients had been on HD more than 6 months and none had received a blood transfusion or iron therapy in previous 6 months. The patients were divided into three groups according to the baseline haematocrit (Ht) and serum ferritin (FTN) levels as a marker of body iron stores: IVIR group (Ht<30% and FTN<100 ng/ml; n=7); High FTN group (Ht>or=30% and FTN>or=100 ng/ml; n=11); and low FTN group (Ht>or=30% and FTN<100 ng/ml; n=9). The IVIR group patients received 40 mg of ferric saccharate i.v. after each HD session until Ht increased by 5%. Serum 8-OHdG and other parameters were prospectively monitored for 10 weeks. RESULTS: At baseline, the serum ferritin level was independently associated with 8-OHdG in a multiple regression model (total adjusted R2=0.47, P<0.01). All patients in the IVIR group achieved the target Ht level during the study. IVIR administration resulted in significant increases in 8-OHdG levels (0.22+/-0.07-0.50+/-0.16 ng/ml: baseline to 10 week) as compared with both the high FTN group (0.52+/-0.20-0.58+/-0.28 ng/ml) and the low FTN group (0.39+/-0.11-0.36+/-0.11 ng/ml) (ANOVA for repeated measures P<0.01). Additionally, serum 8-OHdG and serum ferritin changed in the same manner. CONCLUSIONS: Repeated IVIR administration for HD patients was associated with signs of increased oxidative DNA injury, as reflected by increased serum levels of 8-OHdG. As these changes were accompanied by increased serum ferritin levels, excess body iron stores might play an important role in oxidative stress.     

A comparison of the clinical utility of the radioimmunoassay, high-performance liquid chromatography, and TDx cyclosporine assays in outpatient renal transplant recipients

Rapid and precise cyclosporine measurements are necessary to maximize immunosuppression and minimize toxicity. The new cyclosporine and metabolites TDx fluorescent polarization immunoassay was studied to determine its precision, sensitivity, and stability. Further, it was compared with the existing radioimmunoassay and high-performance liquid chromatography assays for clinical utility. The TDx procedure utilizes 50 microliter of serum or blood. The range of the assay is 0-1000 ng/ml for serum and 0-2000 ng/ml for whole blood. Precision studies of three control levels provided coefficients of variation of 2.1-5.8% for both assays. The sensitivities of the assays were less than 25 ng/ml for serum and less than 50 ng/ml for whole blood. In order to compare the TDx with the currently used RIA and HPLC methods, 362 simultaneous whole blood and serum samples were obtained from 122 renal transplant recipients over a 4-month period. The serum and whole blood TDx assays excluded fewer patients than either the RIA or HPLC assays with regard to sensitivity. The mean serum cyclosporine concentration for samples above the sensitivity was as follows: TDx 120 +/- 5 ng/ml, RIA 116 +/- 4 ng/ml, and HPLC 100 +/- 5 ng/ml. The mean whole-blood cyclosporine concentration for samples above the sensitivity was as follows: TDx 585 +/- 19 ng/ml, RIA 543 +/- 14 ng/ml, and HPLC 178 +/- 5 ng/ml. Serum and blood TDx levels correlated well with RIA levels, with regression coefficients of r = 0.813 and r = 0.897, respectively. Serum and blood TDx levels did not correlate strongly with HPLC levels, with regression coefficients of 0.332 and 0.781, respectively. Seventeen patients were diagnosed as having acute cyclosporine nephrotoxicity. The serum and whole-blood cyclosporine concentrations in these patients were at the upper end of the therapeutic range for all analytical methods. Five patients had acute cellular rejection; serum and whole-blood cyclosporine levels in these patients did not differ significantly from the stable patients when measured by each of the analytical methods. In conclusion, the TDx cyclosporine and metabolites assay provides reliable blood and serum concentrations that correlate well with RIA measurements in renal transplant recipients. This assay offers rapid sample turn-around times making possible same-day results for all patients without putting great demands upon the laboratory.     

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.     

Impairment of phagocyte oxidative metabolism in hemodialyzed patients with iron overload

In order to study the influence of iron overload on the polymorphonuclear leucocyte (PMN) metabolism of patients on chronic hemodialysis, generation of superoxide anion (O2-) by PMN in whole blood was compared in two groups of hemodialyzed patients: group A consisted of twenty-one individuals with serum ferritin levels above 1000 ng/ml and group B of nineteen individuals with serum ferritin levels below 1000 ng/ml. Whereas basal production of O2- was similar in the two groups (6.3 +/- 4.6 vs 11.5 +/- 8.3 nmoles O2- 10(6) granulocytes-1 15 min-1) (mean +/- s.e.m.), PMN response to opsonized zymosan was significantly lower in group A as compared with group B (86.5 +/- 6.3 vs 120.4 +/- 8.2 nmoles O2- 10(6) granulocytes-1 15 min-1) (p less than 0.01). Superoxide anion generation induced by the dialysis procedure was reduced in eight patients from group A (89.2 +/- 32.1) as compared with eight patients from group B (374.3 +/- 100.0 nmoles O2- 10(6) granulocytes-1 15 min-1) (p less than 0.05). These data suggest that iron overload may be involved in the impairment of neutrophil phagocytosis in patients on chronic hemodialysis.     

Iron Overload After Pediatric Liver Transplantation: A Case Report

Iron is an essential nutrient for living cells; however, an excessive accumulation of iron leads to organ damage and directly affects systemic immunity. Iron overload is clinically classified as hereditary or secondary. Most of secondary iron overload is caused by frequent blood transfusions because there is no active mechanism to excrete iron from the body. As recommended in various guidelines, chelation therapy is effective for reducing iron burden and improving organ function. There have been few reports on iron overload through blood transfusion during the perioperative period of liver transplantation. This report presents a case of iron overload due to repeated transfusions after pediatric liver transplantation managed by chelation therapy. The patient, an 11-month-old female with biliary atresia, underwent living donor liver transplantation. She revealed refractory anemia and required frequent blood transfusion. Both serum ferritin and transferrin saturation tended to increase after repeated transfusions, leading to secondary iron overload. Iron chelation therapy was started to prevent progression to organ failure and infection due to iron overload, and yielded a favorable outcome. It is crucial to consider the possibility of secondary iron overload and to achieve early detection and treatment to avoid progression to irreversible organ damage.