The absorption of iron is disturbed in recombinant human erythropoietin-treated peritoneal dialysis patients

Background. Intravenous iron supplementation is often necessary in recombinant human erythropoietin (r-HuEPO)-treated haemodialysis (HD) patients, but rarely in r-HuEPO-treated peritoneal dialysis (PD) patients. This may be due to differences in iron absorption or blood loss. Method. Iron absorption (whole-body counting after ingestion of a radiolabelled iron test dose) and iron metabolism were compared in eight iron-replete r-HuEPO-treated PD patients (serum ferritin 100-500 &mgr;g/l) and 68 healthy iron-replete controls (sufficient iron in bone marrow specimen). Results. Mucosal uptake (13.4±9.8), mucosal transfer (0.34±0.18) and iron retention (4.9±4.0) in PD patients was significantly lower than in controls (42.9±18.8%, P<0.0001, 0.63±0.18, P<0.0001, and 28.0±16.7%, P<0.0001). Conclusion. Iron absorption is impaired in PD patients, as we have shown previously for HD patients. One reason for higher iron needs in HD patients may be higher blood losses due to the dialysis procedure and blood sampling for laboratory tests.     

Serum soluble transferrin receptor reflects erythropoiesis but not iron availability in erythropoietin-treated chronic hemodialysis patients

BACKGROUND: The diagnosis of iron deficiency using the current commonly used tests is usually difficult in hemodialysis patients. Soluble transferrin receptor (sTfR) has caught the attention of physicians recently as regards its use as a parameter for the evaluation of iron status. This study was conducted in order to evaluate the correlation of serum soluble transferrin receptor (sTfR) concentration with hematological parameters and iron profiles, in the role of identifying iron deficiency among dialysis patients. METHODS: Seventy-three patients having received chronic hemodialysis and stable maintenance recombinant human erythropoietin (rHuEPO) therapy were included. Iron, total iron-binding capacity, ferritin and sTfR were measured in the first week. Following this, these patients began to receive intravenous iron dextran (2 mg/kg/week) for 4 weeks. The hematocrit (Hct), hemoglobin (Hb) levels and reticulocyte counts were evaluated weekly. At the beginning of fifth week, the sTfR level was measured again. Patients were classified as belonging to one of the following groups: serum ferritin < 100 microg/L - absolute iron-deficient group; initial ferritin level > or = 100 microg/L with an increase in hemoglobin of greater than 1 g/dL at the end of the study occult iron deficiency group; others - non iron-deficient group. RESULTS: Seventy-one patients completed the study. The concentration of sTfR was positively correlated with Hct, Hb and reticulocyte index at the beginning (r = 0.236, p = 0.047; r = 0.257, p = 0.04; r = 0.401, p < 0.01, respectively) and at the end of the study (r = 0.384, p < 0.01; r = 0.338, p < 0.01; r = 0.427, p < 0.001, respectively). After 4 weeks of iron and rHuEPO therapy, the sTfR concentration increased, rather than declined, from 21.85 +/- 8.06 nM to 23.76 +/- 7.42 nM (p = 0.04) and the change was positively correlated with the changes in Hct, Hb and reticulocyte index. The administered rHuEPO doses did not differbetween the iron deficiency group (absolute deficiency, n = 3; occult deficiency, n = 10) and non-iron deficiency group (n = 58). The sTfR levels failed to identify the occult iron deficiency group because there was no difference between occult iron-deficient and non-iron-deficient patients (24.73 +/- 9.09 nM versus 21.60 +/- 7.89 nM, p = 0.34). Instead, transferrin saturation (TS) could be a differential marker between the 2 groups (19.0 +/- 10.9% versus 30.1 +/- 12.7%, p = 0.012). CONCLUSION: The serum sTfR concentration is indeed an appropriate marker for erythropoiesis. The erythropoitic effect of administered rHuEPO could mask the effect of iron status on the sTfR concentration. This might make the sTfR concentration no longer an appropriate index to identify the presence of occult iron deficiency. Thus, TS and ferritin currently remain better methods for the evaluation of iron status in rHuEPO-treated chronic hemodialysis patients.     

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.     

Silicon and aluminium interactions in haemodialysis patients

Background: Aluminium toxicity in dialysis patients is well described. Aluminium has a close chemical affinity with silicon. Silicon may have a role in protection against aluminium toxicity. Methods: We measured serum aluminium and silicon levels from haemodialysis patients from four different centres. Results: Though no relationship was seen across all centres combined, in one centre there was a reciprocal relationship in patients on home haemodialysis (who did not require reverse osmosis). Median (range) aluminium levels were higher, 2.2 (0.4-9.6) &mgr;mol/l when serum silicon was less than 150 &mgr;mol/l, and lower, 1.1 (0.2-2.8) &mgr;mol/l when serum silicon levels were greater than 150 &mgr;mol/l (P=0.03). Conclusions: In patients treated by haemodialysis without reverse osmosis high serum silicon concentrations were associated with lower serum aluminium concentrations than those with low serum silicon. Further work needs to confirm a preventative role for silicon in the accumulation and subsequent toxicity of aluminium in dialysis patients.     

Relative roles of intestinal absorption and dialysis-fluid-related exposure in the accumulation of aluminium in haemodialysis patients

Background: A recent retrospective study has clearly demonstrated a reduction of cases with positive bone aluminium (A1) staining in the Italian dialysis population, which in general has had a low prevalence of bone A1 toxicity. In the present study we tried to better address the relative role played, in our study population, by enteral and parenteral exposure to A1 in reducing bone accumulation. Methods: We retrospectively examined the data of 105 DFO tests and bone A1 determinations performed in dialysis patients from 1984 to 1995. Enteral exposure was analysed by accurate anamnestic records, while parenteral exposure was evaluated by the determination of A1 content in dialysis fluids. Bone A1 content was assayed chemically and histochemically, while serum A1 was assayed spectrophotometrically. Data pertinent to the patients were allotted into three period groups: 1984-1987; 1988-1991; 1992-1995. As for A1 concentrations in dialysis fluids, the interval 1980-1983 (immediately before the start of our study), which could clearly have influenced bone A1 content, was also considered. Results: Basal serum A1 showed some fluctuations (42.7±34.1; 24.8±21.9 and 38.9±224.9 &mgr;g/l respectively in the three groups, ANOVA P <0.01) but only values of the period 1988-1991 were significantly lower than those of the period 1984-1987 (P <0.05). Increments after the DFO did not differ in the three periods (136.5±105.7; vs 98.7±91.7 and 106.1±96.2 &mgr;g/l respectively, P=n.s). Enteral exposure to drugs containing A1 was comparable (4.1±2.9 vs 4.0±4.6 and 5.8±7.9 total kg ingested respectively; P=n.s.), but bone A1 was dramatically reduced (from 60.7±43.0 to 29.0±24.4 and 31.9±29.9 mg/dg/dw respectively; P <0.0001), along with the definite disappearance of Aluminon-positive cases and A1-related bone disease (ARBD) after 1991. Parenteral exposure through the dialysate dropped from a mean 26±14 &mgr;g/l in the 4-year period prior the start of the study (1980-1983) to 9±6 &mgr;g/l in the period 1984-1987 and to 4.9±2.1 &mgr;g/l and 5.0±2.0 &mgr;g/l respectively thereafter (P <0.0001). Conclusions: Despite the persistence of oral exposure to A1, responsible for the observed stability of serum A1 levels, a definite reduction of bone A1 content has been recorded in our dialysis population, and ARBD has disappeared. This result has to be referred essentially to the optimal control of A1 content in dialysis fluids, which is confirmed as a major factor for A1 intoxication. Key words: aluminium hydroxide; aluminium toxicity; bone aluminium; desferrioxamine test; dialysate aluminium; dialysis fluids; haemodialysis      

Serum iron, infection and inflammation; effects on coronary risk

OBJECTIVES: To explore the potential pathways of association between serum iron and coronary heart disease, with major emphasis on factors related to infections and inflammation. DESIGN: A nested case-control study with 215 cases (myocardial infarction or coronary death) and 215 matched controls over 8.5 years. Logistic regression analyses were used to compare relative risks in various serum iron-high sensitive CRP-total leucocyte count-herpes simplex virus-1 antibody categories. RESULTS: Participants with low iron (< 17 micromol/l) had increased coronary risk with Odds Ratio (OR) of 2.1 (95% CI 1.1-3.8). Simultaneous elevation of hs-CRP and leucocyte count increased the risk substantially in those with low iron, OR 9.8 (95% CI 3.9-24.4). A combination of high herpes simplex virus-1 antibody level and low iron increased the risk modestly (OR 1.2), but when hs-CRP level was high simultaneously, the OR was 13.1 (95% CI 2.9-60.1). CONCLUSIONS: Our data suggest an association between low serum iron level and coronary risk. The association is not independent, but is related to the fact that chronic infections and inflammation are accompanied with low serum iron.     

The effects of megestrol acetate on nutrition,inflammation and quality of life in elderly haemodialysis patients

International Urology and Nephrology - Malnutrition, inflammation and poor quality of life are prevalent among elderly haemodialysis patients. Megestrol acetate (MA) is a synthetic progestin that...     

Glycoxidation and inflammation in chronic haemodialysis patients.

BACKGROUND: Uraemia and haemodialysis treatment are associated with microinflammation and oxidative as well as carbonyl stress, which result in enhanced formation of glycoxidation products. Although both glycoxidation and inflammation can contribute to severe vascular and cardiovascular complications, the role that these pathogenic mechanisms play in the complex response of the whole organism remains to be elucidated. METHODS: We performed a cross-sectional study in 34 clinically stable chronic haemodialysis patients and in 14 healthy controls while determining serum concentrations of pentosidine, fluorescent advanced glycation end-products (AGEs), advanced oxidation protein products (AOPPs) and acute phase reactants. We further assessed the relationship between these glycoxidation products and parameters of inflammation. RESULTS: Glycoxidation products as well as certain acute phase reactants were elevated in haemodialysis patients. There were significant correlations between AOPPs and inflammatory parameters such as orosomucoid (0.39, P < 0.05), fibrinogen (0.49, P < 0.05) and pregnancy-associated protein A (PAPP-A; 0.46, P < 0.05), but no correlations between pentosidine or fluorescent AGEs and any of the inflammatory parameters. CONCLUSION: Oxidative damage showed a closer relationship to inflammation than advanced glycation (glycoxidation). AOPPs may represent a superior acute biochemical marker, whereas AGEs may better describe chronic long-lasting damage.     

Liver disease vs systemic inflammation in haemodialysis patients.

Sir, The direct association between elevated liver enzymes and serumC-reactive protein (CRP) was recently reported in subjects withmetabolic syndrome [1]. This indicates that even mild liverdisease contributes to generalized low-grade inflammation and,in consequence, may enhance cardiovascular risk. Chronic inflammationis common in patients undergoing maintenance haemodialysis (HD)therapy, and deleteriously underlies the progression of malnutritionand atherosclerosis [2]. Renal failure is also an instructivemodel of the metabolic syndrome, with its harmful effects onboth the cardiovascular system and liver [2]. In addition, chronicviral hepatitis may affect     

The role of aluminium and parathyroid hormone in erythropoietin resistance in haemodialysis patients

Recombinant human erythropoietin (rHuEpo) is an effective therapy for anaemia in most patients with end-stage renal disease (ESRD). However, there remain a minority of patients with ESRD who are resistant to the effects of rHuEpo. The present study examined the role of aluminium overload and hyperparathyroidism of the biological effects of rHuEpo. Twenty-two patients aged 26-74 (mean 53 +/- SD 15.5) received rHuEpo 50-200 U/kg per week for 16.5 +/- 8.0 months (range 3-27). Haemoglobin was maintained at 11.5-13.0 g/dl by appropriate dose adjustment. Iron supplements were provided to maintain serum ferritin greater than 200 ng/ml. The mean time to rHuEpo response (Hb greater than 2 g/dl over baseline) was 6.1 +/- 2.6 weeks. Mean pretreatment serum aluminium correlated with time to Hb response (r = 0.48; P less than 0.05) and pretreatment mean corpuscular volume (r = 0.43; P less than 0.05) but not with eventual rHuEpo maintenance dose. PTH did not correlate with either Hb response or eventual maintenance rHuEpo dose. In summary, elevated serum aluminium concentrations were associated with an initial resistance to the biological effects of rHuEpo but had no effect on long-term dose requirements. In contrast, no impact of PTH on either immediate or long-term rHuEpo dose was evident.     

Safety of intravenous injection of iron saccharate in haemodialysis patients

BACKGROUND.: The most frequent i.v. iron preparations used for haemodialysispatients are iron dextran, iron gluconate and iron saccharate.Possible side effects include anaphylactic reactions due topreformed antibodies to dextran or vascular reactions due tounbound iron during treatment with iron gluconate or iron saccharate. METHODS.: Four dosage regimens of i.v. iron saccharate therapy were studied:10, 20, 40 and 100 mg, which were given over a time period of1 min after the end of the dialysis session. Iron metabolismparameters (serum iron concentration, transferrin saturationand serum ferritin levels) were measured at 0, 1, 5, 15 and30 min after application and immediately prior to the next dialysissession. All 18 regular haemodialysis patients studied receivedrecombinant human erythro-poietin (rHuEpo). RESULTS.: Serum iron levels and transferrin saturation increased significantlyfollowing i.v. injection of all doses of iron saccharate. Iron‘oversaturation’ of transferrin iron binding didnot occur in patients with transferrin levels >180 mg/dl.However, in patients with transferrin levels <180 mg/dl theinjection of 100 mg iron saccharate resulted in a transferrinsaturation of 102.6±39.5% (two patients with transferrinlevels of 87 and 92 mg/dl had transferrin saturations of 119.8and 149.7%, two patients with transferrin levels of 148 and171 mg/dl had transferrin saturations of 77.9 and 63.1%, respectively).Serum ferritin levels remained unchanged during the post-injectionperiod and increased by the next dialysis session followinginjection of 100 mg iron saccharate by 165%. CONCLUSIONS.: It is concluded that intravenous iron saccharate injection (10–100mgeven within 1 min) does not result in ‘oversaturation’of transferrin iron binding if serum transferrin levels are>180mg/dl (high-risk patients: transferrin <100 mg/dl). Thismay explain, at least in part, the minimal side effects observedduring the i.v. application of iron saccharate. Low-dose i.v.iron saccharate (10–40 mg) is recommended for iron supplementationof haemodialysis patients. If injection of 100 mg is necessary,serum transferrin level should exceed 180 mg/dl. There is, however,no need for fast i.v. injection during routine iron supplementation.     

Efficacy of low‐dose i.v. iron therapy in haemodialysis patients

Aim: i.v. iron therapy is more effective in maintaining adequate iron status in haemodialysis (HD) patients than oral iron therapy (OIT). However, data on lower doses of i.v. iron therapy are insufficient. Methods: A non‐randomized, open‐label study was performed to compare the efficacy of low‐dose (≤50 mg/week of iron sucrose) i.v. iron therapy (LD‐IVIT) with OIT in HD patients with 100–800 µg/L serum ferritin levels over 4 months. Results: Eighty‐nine patients in the LD‐IVIT group (40 men, 49 women; aged 61 ± 13 years) and 30 patients in the oral iron therapy group (17 men, 13 women; aged 59 ± 7 years) were evaluated. After 4 months of each treatment, serum ferritin levels increased from 398 ± 137 to 529 ± 234 µg/L in the LD‐IVIT group (P < 0.01) but decreased from 351 ± 190 to 294 ± 175 µg/L in the OIT group (P < 0.01). In the LD‐IVIT group, transferrin saturation (from 28% ± 11% to 30% ± 14%, P = 0.49), weekly doses of recombinant human erythropoietin (from 5822 ± 2354 to 5636 ± 2306 IU/week, P = 0.48) and haemoglobin (from 101 ± 9 to 103 ± 9 g/L, P = 0.15) levels remained stable. Conclusion: LD‐IVIT may be one of the regimens that may be considered for maintaining iron status in HD patients. However, efficacy of LD‐IVIT should be verified by further randomized study.     

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.     

Relationship between plasma levels of zonulin,bacterial lipopolysaccharides,d-lactate and markers of inflammation in haemodialysis patients

International Urology and Nephrology - Increased permeability of the intestinal wall and intestinal dysbiosis may contribute to chronic systemic inflammation, one of the causes of accelerated...