Kinetics of aluminoxamine and feroxamine chelates in dialysis patients.

To achieve a rational basis for the use of deferoxamine (DFO) in aluminum (AL) -and iron (Fe)-overloaded uremic patients, important insights may be provided by the recently available micromethods to determine DFO and its metallochelates aluminoxamine (AlA) and feroxamine (FeA). With this procedure, AlA and FeA plasma kinetics were evaluated in a pilot study in 10 uremic patients during a whole week after a single DFO infusion performed during the first hour of the first standard bicarbonate hemodialysis (HD) of the week. Patients were divided into normal (n = 6) and high (n = 4) ferritin groups (1 and 2 respectively). Baseline Al concentrations were greater than 2 less than 6 in group 1 and less than 1.5 mumol/l in group 2. DFO was given at doses of 40, 20 and 10 mg/kg. AlA and FeA showed substantially different kinetics. AlA kinetics were similar in group 1 and 2: they reached their peak at the beginning of the 2nd HD, decreased during the 2nd and 3rd HD, and with the highest DFO dose still increased between the 2nd and 3rd HD. At similar pre-DFO Al values (greater than 2 less than 3.3 mumol/l), increased DFO doses produced increased AlA concentrations ranging from 95 to 40% of total plasma Al for all the week. At higher pre-DFO Al values (greater than 3.5 less than 6 mumol/l), even a DFO dose as low as 10 mg/kg was sufficient to form consistent AlA amounts (from 80 to 15% of total Al).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of body iron stores on serum aluminum level in hemodialysis patients.

To evaluate the influence of body iron stores on the serum aluminum (Al) level, we studied the correlation between iron status (the serum ferritin, serum iron and transferrin saturation) and serum Al levels in 68 severely anemic hemodialysis patients. Among them, 36 underwent the desferrioxamine (DFO) mobilization test. These 68 patients were divided into three groups according to their serum ferritin level. The basal Al level in the patient group was 41.4 +/- 37.4 micrograms/l (control, 4.1 +/- 2.4 micrograms/l). The serum Al level after DFO infusion of the patient group was 111.1 +/- 86.8 micrograms/l. A significantly higher basal Al and peak Al level after DFO infusion were found in group 1 patients (serum ferritin less than 300 micrograms/l) when compared to group 2 (serum ferritin 300-1,000 micrograms/l) and group 3 (serum ferritin greater than 1,000 micrograms/l) patients. A significant negative correlation between serum ferritin and basal serum Al (r = -0.544, p = 0.0001), as well as peak serum Al after DFO infusion (r = -0.556, p = 0.0001), was noted. Similarly, a negative relationship between serum Al (both basal and peak) and either serum iron or transferrin saturation was noted. However, there was no correlation between the serum Al level and the dosage of aluminum hydroxide. In conclusion, serum ferritin, serum iron and transferrin saturation were inversely correlated with serum Al in our hemodialysis patients. Iron deficiency may probably increase Al accumulation in these patients.     

Removal of trace metals by continuous ambulatory peritoneal dialysis after desferrioxamine B chelation therapy.

We studied the removal of aluminum (Al), iron (Fe), copper (Cu), lead (Pb) and zinc (Zn) with continuous ambulatory peritoneal dialysis, before and after desferrioxamine B (DFO) administration (2 g intravenously) in two patients with chronic renal failure and Al-related osteopathy. Both patients had 4 peritoneal dialysis exchanges (2 liters each) per day. Blood concentrations of Al increased 413% (patient A) and 190% (patient B) after DFO. Patient B had a 15% increase in Fe; other metals remained unchanged. Dialysate efflux Al concentrations had peak post-DFO increments of 761% and 840% in patients 1 and 2, respectively. Peak post-DFO increments in Fe dialysate concentration were 342% and 89.5% in the respective patients. Dialysate/plasma (D/P) concentration ratios of Al increased from pre-DFO levels (mean +/- SEM) of 0.370 +/- 0.048 to 0.523 +/- 0.061 after DFO; similarly, Fe D/P ratios increased from 0.259 +/- 0.053 to 0.446 +/- 0.075 with DFO therapy. These results indicate an increase in the ultrafiltrable proportion of Al and Fe in plasma after DFO administration. During 3 days after DFO, patient 1 had a total removal of Al and Fe of 2.9 mg and 4.9 mg, respectively. Metal removal in patient 2 was 7.6 mg of Al and 2.7 mg of Fe. Peritoneal extraction of other trace metals was minor.     

Aluminium interference in the treatment of haemodialysis patients with recombinant human erythropoietin

In nine chronic haemodialysis patients a desferrioxamine (DFO) load test (40 mg/kg body-weight) was performed 1 year after the beginning of treatment with recombinant human erythropoietin (rHuEpo). The patients were then divided into two groups. Group A comprised five patients with a greater mean aluminium (204 +/- 28 micrograms/l) than the four patients in group B. Group A was given a mean dose of 25.8 g (range 14-39 g) of DFO over 6 months. Group B (aluminium values 112 +/- 36 micrograms/l) was never treated with DFO. During the period of observation, plasma iron, serum ferritin and transferrin, as well as iron supplementation, did not differ between the groups. After DFO treatment a second DFO load test was performed. The mean predialysis aluminium value was significantly reduced in group A (204 +/- 28 vs 111 +/- 72 micrograms/l; P less than 0.05), while remaining unchanged in group B (112 +/- 36 vs 140 +/- 39 micrograms/l; P = ns). In both groups, the doses of rHuEpo necessary to maintain the same haemoglobin values decreased with time, but reduced significantly only in group A (298 +/- 105 vs 110 +/- 61 mu/kg per week; delta -63%; P less than 0.01). Thus, aluminium interferes with the response to rHuEpo in haemodialysis patients, and the correction of aluminium overload with DFO can allow a considerable sparing of rHuEpo.     

Rapid removal of DFO-chelated aluminum during hemodialysis using polysulfone dialyzers

Aluminum (Al) removal following deferoxamine (DFO) therapy in hemodialysis patients was evaluated in a paired-fashion comparing cuprophane (Travenol 12.11) and polysulfone (Fresenius F-80) dialyzers. QB and QD were held constant at 250 and 500 ml/min, respectively. The polysulfone dialyzer increased total plasma Al clearance from 20.0 +/- 2.8 to 80.5 +/- 7.6 ml/min (P less than 0.01), and reduced the t 1/2 of plasma Al during hemodialysis from 538 +/- 113 to 112 +/- 12 min (P less than 0.01). The polysulfone F-80 dialyzer increased Al removal during the first hour of hemodialysis from 518 +/- 191 to 1812 +/- 720 micrograms/hr (P less than 0.01). During a four hour hemodialysis the F-80 dialyzer returned plasma Al levels to pre-DFO values (103 +/- 36 vs. 93 +/- 23, P less than 0.05), suggesting complete removal of the DFO chelated Al complex. In one patient Al removal was evaluated using cuprophane, F-40, F-60 and F-80 dialyzers and the t 1/2 for Al removed decreased from 484.6 to 276.1 and 108 to 99 minutes, respectively. These data show the Fresenius F-80 polysulfone dialyzer effects the rapid removal of DFO-Al complexes. We propose use of the Fresenius F-80 dialyzer in conjunction with reduced DFO doses and i.m. administration of DFO the day prior to dialysis to limit DFO exposure as a method to decrease DFO-related side-effects in hemodialysis patients.     

Comparative evaluation of bone aluminum content and bone histology in patients on chronic hemodialysis and hemofiltration

In order to compare hemofiltration (HF) and hemodialysis (HD) in connection with the risk of aluminum overload and renal osteodystrophy, double bone biopsies after double tetracycline labeling and a desferrioxamine test were performed in 12 patients on HF and 15 patients on HD. The aluminum concentration was low (less than 0.6 mumol/l) both in the dialysate and the substitution fluid. The duration of treatment (about 2 years) and the cumulative doses of Al(OH)3 and CaCO3 were comparable in the two groups. None of the patients was taking 1 alpha-OH-D. The aluminum balance during an HF run ranged from -22 to +1.8 mumol/l, the balance being positive only when the plasma aluminum was less than 0.5 mumol/l. Basal plasma aluminum and its increase induced by desferrioxamine were comparable in the two groups. Bone aluminum content was also comparable, but was about 10 times higher than in 7 nonuremic controls. Bone aluminum content and plasma aluminum increase after desferrioxamine were correlated to the Al(OH)3 cumulative dose. None of the patients had florid osteomalacia with increased osteoid thickness, and only 1 in each group had traces of stainable aluminum. The mineralization front was decreased in 8 of 12 HF and in 9 of 14 HD patients, so that no difference was observed between the means of the two groups. The predominant histological bone picture of the patients was osteitis fibrosa which was present in 10 of 12 HF and in 13 of 15 HD patients. Mean osteoclast count and active resorption surface were comparable in the two groups, but was increased (5-10 times the mean of the controls).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevention and treatment of aluminum overload in uremic patients: long-term results

The authors evaluate the efficacy of a protocol of prevention and treatment of aluminum (Al) overload in RDT patients during a 7-year period (from 1981, 164 patients, to 1987, 161 patients). Al in dialysate solutions was always less than 25 micrograms/l. Baseline Al levels greater than 100 micrograms/l were found in 22% of patients in 1981 but in none in 1987, while the percentage of values less than 60 micrograms/l increased from 55 to 91%. DFO tests were positive in 54% and 7% of cases in 1981 and 1987, respectively. A clinical diagnosis of Al intoxication was performed in 6 patients in 1981, and no further cases were diagnosed later. DFO treatment (50 mg/kg once a week) was employed preventively in 31 patients owing to positive DFO-tests, and in the 6 Al-intoxicated patients therapeutically. In the former patients none developed clinical intoxication. In the latter group clinical improvement was only temporary in the three parathyroidectomized patients. Al hydroxide [Al(OH)3] as a phosphate binder was tapered off in 1981 and substituted by Al-free chelants. In 1987, 66% of patients were given CaCO3 or Mg (OH)2 alone or in association, while 34% still needed Al(OH)3, although at low dosages (less than 2 g/day). The conclusion is that such a protocol is able to prevent and to treat cases of Al intoxication, albeit only partially.     

The diagnostic critical value in DFO low dose loading test on patient with aluminum accumulation compared to each parameter of ROD

One hundred two hemodialyzed patients were examined to determine the standard level of delta Al value which is the difference of serum Al concentrations between pre and post DFO loading test. We applied low dose of DFO 15 mg/kg in this loading test. Some significant negative correlations were found between delta Al and MCI, sigma GS/D, osteocalcin, free-Hydroxyproline (dialysate) and free-gamma-Carboxyglutamic acid (dialysate). Each correlation rate was -0.58, -0.44, -0.76, -0.57 and -0.51 respectively. In addition tendencies of correlation were found between delta Al and ALP and between delta Al and %QCT (QCT/mean QCT in patient's age x 100). And statistical significant differences were found between (0 less than delta Al less than or equal to 150 micrograms/l) group and (150 micrograms/l less than delta Al) group in each osteobiochemical parameter. These results indicate that 150 micrograms/l is the lower diagnostic standard level of delta Al in 15 mg/kg DFO loading test.     

High deposition rate of aluminum in tissues in diabetic hemodialysis patients

Aluminum (Al) accumulation in bone is a serious problem in patients on hemodialysis. We studied deferoxamine infusion test (DFO test) in 14 diabetic patients on hemodialysis (HDDM) and 23 hemodialysis patients originated from glomerulo nephritis (HDCGN) to determine whether Al accumulation is different between the two groups or not. There was no difference in hemodialysis duration and total oral intake of Al containing drugs between two groups. Serum C-terminal parathyroid hormone (C-PTH) in HDDM was lower than that in HDCGN group (1.82 +/- 1.30 vs. 3.80 +/- 1.82 ng/ml; P less than 0.01). However serum Al (s-Al) levels were comparable (61.9 +/- 53.0 vs, 45.0 +/- 32.3 micrograms/l). A significant correlation was observed between duration of dialysis period and s-Al in HDDM (r = 0.806, p less than 0.01), but in HDCGN, the relation was not significant. The patients in HDDM whose cumulative aluminum intake was less than 2.0 kg showed the higher serum A1 concentrations before DFO and greater increases in s-Al after DFO test, as compared with those in HDCGN with matched aluminum intake (93.8 +/- 67.6 vs. 35.9 +/- 23.6 micrograms/l; p less than 0.001 and 141.2 +/- 81.8 vs. 70.3 +/- 41.1 micrograms/l; p = 0.035). These results indicate that in uremic diabetic patients with lower intake of Al containing drugs, an early accumulation of Al in the whole body occurs possibly because of the enhanced absorption rate of Al at an intestine and/or the low PTH level.     

The effect of an iron supplement on serum aluminum level and desferrioxamine mobilization test in hemodialysis patients.

BACKGROUND: The serum aluminum (Al) measurement with desferrioxamine (DFO) mobilization is a screening test for uremic patients with an Al overload. In these patients, body iron status is one of the factors affecting the serum Al level. This study is designed to elucidate the effects of iron supplements on the serum Al and the DFO mobilization test. METHODS: Our study featured ten hemodialysis patients with iron deficiency anemia. The iron supplement was given intravenously with saccharated ferric oxide, 40 mg three times weekly, at the end of each hemodialysis. The total amount of iron supplement was 1,000 mg. All the patients underwent a DFO test at a dose of 5 mg/kg. The same test was repeated two weeks after completion of the iron supplement. RESULTS: After the iron supplement, patients' iron deficiency anemia improved with a serum ferritin elevation from 312.4 +/- 589.5 to 748.2 +/- 566.2 microg/L (p < 0.01), and iron saturation from 21.6 +/- 20.3 to 41.1 +/- 21.7% (p = 0.06). The basal serum Al level decreased from 34.3 +/- 13.8 to 21.8 +/- 8.5 microg/L (p = 0.01). In the DFO mobilization test, the peak serum Al level decreased from 63.4 +/- 19.3 to 50.7 +/- 20.5 microg/L (p < 0.01). The amount of Al increment (deltaAl) in DFO test was not changed (29.1 +/- 12.0 vs. 28.9 +/- 15.9 microg/L, p = 0.86). The change in basal Al level tended to negatively correlate with the percentage of increment in iron saturation (r = -0.628, p = 0.05). CONCLUSION: Results in this study suggest that iron supplements may significantly reduce the basal serum Al and peak Al in DFO mobilization test, without significant change of the mean deltaAl. The data presented indicate that in the interpretation of serum aluminum levels the iron status should be taken into account.     

Effects of ascorbic acid and pyridoxine supplementation on oxalate metabolism in peritoneal dialysis patients.

We studied the effect of vitamin C and B6 supplementation on oxalate metabolism in seven patients receiving chronic peritoneal dialysis therapy. The study was divided into three phases, each lasting 4 weeks. Plasma oxalate, total ascorbic acid, and pyridoxal-5'-phosphate (PLP) were measured at the end of each phase. Twenty-four-hour urinary excretion and dialysate removal rates of oxalate were also obtained. At the end of phase I (supplement-free period), plasma oxalate levels were markedly elevated at 47.6 +/- 7.1 mumol/L (437 +/- 66 micrograms/dL) (normal, 3.4 +/- 0.4 mumol/L [30.3 +/- 1.6 micrograms/dL]). Plasma total ascorbic acid levels were 62 +/- 6 mumol/L (1.0 +/- 0.1 mg/dL) (normal, 45 to 57 mumol/L [0.8 to 1.0 mg/dL]), while plasma PLP levels were markedly reduced to 24 +/- 5 nmol/L (normal, 40 to 80 nmol/L). Daily supplements of 0.57 mmol (100 mg) ascorbic acid orally (phase II) resulted in a 19% increase in the plasma oxalate levels to 57.8 +/- 6.1 mumol/L (520 +/- 55 micrograms/dL) (P less than 0.03), with a concomitant 60% increase in the plasma ascorbate levels (91 +/- 6 mumol/L [1.6 +/- 0.1 mg/dL], P less than 0.01). Plasma PLP values remained low. Finally, during phase III (0.57 mmol or 100 mg ascorbic acid plus 59.6 mumol or 10 mg pyridoxine HCI orally daily), plasma oxalate levels declined by 17% to 47.9 +/- 5.2 mumol/L (431 +/- 47 micrograms/dL) (P greater than 0.05 v phase II).(ABSTRACT TRUNCATED AT 250 WORDS)     

Removal of aluminum during hemodialysis: effect of different dialyzer membranes

Aluminum toxicity is now widely recognized as a major cause of morbidity in patients on maintenance hemodialysis. Desferrioxamine (DFO) chelation therapy has been suggested as a method of AI removal in such patients, though the most appropriate treatment schedule is yet to be established. In the present study, AI removal following DFO infusion was evaluated using two different dialyzer membranes to test the hypothesis that polyacrilonitrile (PAN) membranes permit better AI clearance. All patients studied had significantly elevated plasma AI concentrations (1.22 to 9.45 mumol/L; normal less than 0.56 mumol/L). Plasma AI did not correlate with estimated total AI intake. During hemodialysis with a cuprophane membrane, AI clearance ranged from 33.5 to 42.1 mL/min. Total AI removal was 192.2 +/- 90.4 mumol during cuprophane dialysis. During hemodialysis with a PAN membrane, AI clearance ranged from 35.7 to 54 mL/min. Total AI removal was 154.2 to 93.9 mumol during PAN dialysis. The differences in AI clearance and total AI removal were not statistically significant. It is concluded that use of a PAN membrane does not significantly enhance DFO-AI clearance.     

Deferoxamine test and PTH serum levels are useful not to recognize but to exclude aluminum-related bone disease.

The use of noninvasive diagnostic tools, like the deferoxamine (DFO) test and serum iPTH, to identify aluminum-related bone disease has proved to be inadequate due to false-negative cases; therefore, bone biopsy becomes a necessary diagnostic procedure. Our purpose was to verify whether these non-invasive parameters, appropriately used, may result valid in the identification of patients not at risk of Al toxicity, therefore restricting the need for histologic evaluation. We studied 68 hemodialyzed patients, aged 49.0 +/- 11.6 years, with a M/F ratio of 37/31 and a dialytic age of 85.0 +/- 47.0 months, by means of bone biopsy, DFO test and serum C-PTH. 19.1% of the cases had positive stainable Al and/or high bone Al content (greater than 60 mg/kg/dw) and could be intoxicated. To obtain the highest sensitivity, we selected the following limit values: the lower limit of increment so far proposed for DFO test positivity (greater than 150 micrograms/l) and a value capable of selecting patients with pathologic osteoclasia for C-PTH (greater than 15 ng/ml). With these limits, four different groups of patients were recognized: group A, DFO test positive and PTH high, n = 12; group B, DFO test positive and PTH low, n = 6; group C, DFO test negative and PTH high, n = 30; group D, DFO test negative and PTH low, n = 20. In group B, which could be anticipated as being at higher risk, we actually found the highest (p less than 0.05) bone Al content as compared to other groups, associated with a reduced bone formation rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

THE EFFECT OF AN IRON SUPPLEMENT ON SERUM ALUMINUM LEVEL AND DESFERRIOXAMINE MOBILIZATION TEST IN HEMODIALYSIS PATIENTS

Background. The serum aluminum (Al) measurement with desferrioxamine (DFO) mobilization is a screening test for uremic patients with an Al overload. In these patients, body iron status is one of the factors affecting the serum Al level. This study is designed to elucidate the effects of iron supplements on the serum Al and the DFO mobilization test. Methods. Our study featured ten hemodialysis patients with iron deficiency anemia. The iron supplement was given intravenously with saccharated ferric oxide, 40 mg three times weekly, at the end of each hemodialysis. The total amount of iron supplement was 1,000 mg. All the patients underwent a DFO test at a dose of 5 mg/kg. The same test was repeated two weeks after completion of the iron supplement. Results. After the iron supplement, patients' iron deficiency anemia improved with a serum ferritin elevation from 312.4 ± 589.5 to 748.2 ± 566.2 μg/L (p < 0.01), and iron saturation from 21.6 ± 20.3 to 41.1 ± 21.7% (p = 0.06). The basal serum Al level decreased from 34.3 ± 13.8 to 21.8 ± 8.5 μg/L (p = 0.01). In the DFO mobilization test, the peak serum Al level decreased from 63.4 ± 19.3 to 50.7 ± 20.5 μg/L (p < 0.01). The amount of Al increment (ΔAl) in DFO test was not changed (29.1 ± 12.0 vs. 28.9 ± 15.9 μg/L, p = 0.86). The change in basal Al level tended to negatively correlate with the percentage of increment in iron saturation (r = ? 0.628, p = 0.05). Conclusion. Results in this study suggest that iron supplements may significantly reduce the basal serum Al and peak Al in DFO mobilization test, without significant change of the mean ΔAl. The data presented indicate that in the interpretation of serum aluminum levels the iron status should be taken into account.     

The effect of desferrioxamine on concentration and distribution of aluminum in bone

Aluminum (Al) loaded rats were injected chronically with either desferrioxamine (DFO) or saline. Six rats of each treatment group were sacrificed before and after one, three, and nine months of treatment for determination of tissue and serum Al, and for histological localization of bone Al. Urinary Al was measured during one week before sacrifice. Al loading caused significant elevations of bone (136.2 +/- 22.0 micrograms/g) and liver (114.4 +/- 41.9 micrograms/g) aluminum. Serum Al in DFO-treated animals was not different from their controls (216.4 +/- 80.5 and 226.9 +/- 42.9 micrograms/liter after one month; 151.0 +/- 20.8 and 138.0 +/- 63.9 micrograms/liter after three months; 72.1 +/- 40.7 and 61.6 +/- 14.2 micrograms/liter after nine months in control and DFO-treated animals respectively). Urinary Al excretion in the DFO-treated group was increased at all times as compared to the control rats. A decrease of muscle Al occurred after one month of DFO treatment, but no significant differences of liver and bone Al could be shown between DFO-treated rats and their controls. Al decreased to a comparable degree in all tissues of both DFO and control rats after nine months of treatment. Histomorphometric examination of the bones showed that after one and three months of treatment, significantly less Al was localized at the calcification front of DFO-treated rats compared to their controls (75.6 +/- 6.9% and 53.4 +/- 20.9% after one month; 52.3 +/- 10.2% and 34.8 +/- 10.6% after three months in control and DFO rats respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Accelerated removal of deferoxamine mesylate-chelated aluminum by charcoal hemoperfusion in hemodialysis patients

Although deferoxamine mesylate (DFO) is effective in removing aluminum (Al) in hemodialysis patients, treatment with this drug is associated with a number of adverse effects. In order to limit the exposure of patients to DFO-Al complexes, the efficacy of colloidin-coated microencapsulated charcoal cartridges added in series to conventional dialyzers was investigated. The clearances of Al by the sorbent system were initially 116 +/- 4.7 mL/min, but decreased to 42.5 +/- 6.6 mL/min after 120 minutes of treatment. Thereafter, the Al clearances remained constant. In contrast, the Al clearances of the dialyzer were 29.5 +/- 1.8 mL/min initially and did not change during the treatment period. Both the percent and absolute decrease in Al levels after four hours of dialysis were greater with the dialyzers plus carbon cartridges than with the dialyzers alone. This resulted in an increase in the minimum net Al removal from 1,862 +/- 174 micrograms/treatment to 3,007 +/- 43 micrograms/treatment (P less than 0.05). Treatment with sorbent hemoperfusion should be considered in selected hemodialysis patients being treated with DFO for Al overload.     

Desferrioxamine enhances the haemopoietic response to erythropoietin, but adverse events are common.

To determine whether the chelation of aluminium enhances the haemopoietic response to recombinant human erythropoietin (r-HuEPO), desferrioxamine (DFO) at a dose of 20-30 mg/kg was given to 7 of 17 transfusion-dependent haemodialysis patients treated with r-HuEPO (40 units/kg/dialysis i.v.). The two randomly allocated groups did not differ in age, initial haemoglobin, plasma aluminium, plasma aluminium after DFO challenge, and ferritin, but, by chance, dialysis time was longer in the DFO group (69 vs. 32 months; p = 0.02). DFO was administered for 16 +/- 4 (SE) dialyses. During this period, Hb rose faster in the DFO group, in relation to time (0.61 vs. 0.29 g/l day; p less than 0.05) and r-HuEPO dose (3.35 vs. 1.88 g/l/100 units r-HuEPO/kg; p less than 0.05). However, in the DFO group, there was a high incidence of side effects, especially visual toxicity. It is concluded that DFO enhances the effectiveness of r-HuEPO in correcting the anaemia of chronic renal failure, but the combination of DFO and r-HuEPO is unsafe under the conditions described.     

Indirect clinical evidence that 1 alpha OH vitamin D3 increases the intestinal absorption of aluminum

In a previous study we showed that 1 alpha OH vitamin D3 [1 alpha (OH)3] given to 16 hemodialyzed patients taking Al(OH)3 at a constant dose increased their plasma concentrations of aluminum [Demontis et al. 1986]. In order to choose between 2 possible mechanisms explaining this increase (increased intestinal absorption or decreased tissue storage of aluminum), we gave, in the present study, 1 alpha (OH)3 the same dose (6 micrograms per week) for the same period (4 weeks) to 15 stable hemodialyzed patients after their Al(OH)3 had been discontinued for 6 weeks. Under Al(OH)3 treatment they had a mean plasma aluminum (2.33 +/- 2.36 mumol/l) which was not significantly different from that of the patients in our former study (1.23 +/- 0.25 mumol/l). After Al(OH)3 discontinuation, plasma aluminum (measured by inductively coupled plasma emission spectrometry) decreased significantly as early as the 2nd week of the control period (1.39 mumol/l). The decrease was maintained at a plateau throughout the 5 weeks of the control period (1.38 mumol/l), the 4 weeks of 1 alpha OH vitamin (vit) D3 administration (1.40 mumol/l) and the 8 weeks of the post 1 alpha (OH)3 period (1.22 mumol/l). Plasma calcium and phosphate concentrations increased significantly with 1 alpha (OH)3 and decreased thereafter whereas plasma PTH concentrations decreased during 1 alpha (OH)2 D3 and increased after its discontinuation suggesting biological activity of 1 alpha (OH)3. Since 1 alpha (OH)3 increases plasma aluminum in hemodialyzed patients only when they are simultaneously taking Al(OH)3, it is suggested that this increase is explained by an increase of intestinal absorption of aluminum and not by a tissue redistribution of aluminum.     

Aluminum uptake and toxicity in cultured mouse hepatocytes

Hepatic aluminum (Al) accumulation in association with hepatobiliary dysfunction has been described in children receiving contaminated parenteral alimentation solutions and in aluminum-overloaded experimental animals. The mechanisms of hepatic Al uptake are not clearly understood, and it is not known whether Al is directly toxic to the hepatic cell or if toxicity occurs from the effect of Al on hepatic iron (Fe) metabolism. Al causes a microcytic hypochromic anemia and concomitant hepatic Al and Fe can accumulate in dialysis patients, suggesting that Al may alter Fe metabolism. Therefore, Al uptake and toxicity were studied in mouse hepatocytes in culture. Al accumulation, cell growth, media hepatic enzyme concentrations, and cell malonyldialdehyde concentrations, a marker of membrane lipid peroxidation, were measured in mouse hepatocytes grown in media containing either Al citrate, transferrin-Al (Tf-Al), or no additions over 96 h. Al uptake occurred only in cells grown in Tf-Al and Al citrate at 24 h and increased linearly achieving cellular concentrations at 96 h of 522 +/- 36 and 186 +/- 12 micrograms/L, respectively, compared with 31 +/- 3 micrograms/L (P less than 0.001) in control media. Inhibition of cell growth occurred at 48, 72, and 96 h (P less than 0.001), and media lactate dehydrogenase and aspartate aminotransferase concentrations increased starting at 48 and 72 h, respectively (P less than 0.001), only in media containing Tf-Al. Cell malonyldialdehyde levels were significantly higher in Tf-Al-loaded mouse hepatocytes compared with control cells at 96 h (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Synergistic effect of desferrioxamine and recombinant erythropoietin on erythroid precursor proliferation in chronic renal failure.

BACKGROUND: Desferrioxamine (DFO) has been suggested to improve erythropoiesis in end-stage renal failure independently of its aluminium (Al)-chelating effect. A possible synergistic effect of DFO and recombinant human erythropoietin (r-HuEpo) could be very useful in treating anaemia of chronic renal failure. METHODS: In order to verify whether a synergistic action of DFO and r-HuEpo exists, we enrolled 11 patients undergoing chronic haemodialysis and r-HuEpo treatment. All had a negative DFO test, very low serum Al levels (< 20 microg/l), ferritin > 100 ng% and iPTH < 200 pg/l. Samples were drawn for a basal erythroid precursor (burst-forming unit-Erythroid, BFU-E) evaluation. After isolation by Ficoll Hypaque, a 14 day incubation was carried out with: (i) r-HuEpo 3 U/ml; (ii) r-HuEpo 30 U/ml; and (iii) r-HuEpo 30 U/ml + DFO 167 microg/ml. Patients then received 5 mg/kg DFO infused during the last hour of each dialysis session for 12 weeks. New BFU-E evaluations were performed after 2, 6 and 12 weeks of treatment. BFU-E colonies were counted in duplicate with an inverted microscope after 14 days. Haemoglobin (Hb), ferritin, transferrin, reticulocytes, hypochromic erythrocytes, soluble transferrin receptor and serum erythropoietin were also evaluated at the same time. RESULTS: High dose r-HuEpo achieved greater proliferation than low dose r-HuEpo cultures during all phases of the study. At baseline, r-HuEpo and DFO culture had a greater number of colony units than high dose r-HuEpo culture ( 103.7 +/- 50.2 vs 95.1 +/- 50.5, NS). This increase became significant after 2 weeks (145 +/- 59.3 vs 122.9 +/- 59.6, P < 0.02), and remained so at 6 (167.4 +/- 60.3 vs 149 +/- 55.6, P < 0.01) and 12 weeks (191 +/- 64.5 vs 155.1 +/- 56.3, P < 0.01). An increased proliferation was observed after DFO therapy in all culture studies: low dose r-HuEpo culture increased from 69.4 +/- 38.2 to 86.6 +/- 48.5, 115 +/- 39 and 123 +/- 46; high dose r-HuEpo culture increased from 95.1 +/- 50.5 to 122.9 +/- 59, 149 +/- 55.6 and 155.1 +/- 56.3 and r-HuEpo plus DFO culture from 103.7 +/- 50.2 to 145 +/- 59.3, 167 +/- 60.3 and 191 +/- 64.5 at 2, 6 and 12 weeks, respectively (all P < 0.01 by ANOVA). Haemoglobin, reticulocytes and soluble transferrin receptor were slightly increased, while ferritin decreased. Hypochromic erytrocytes were variable. CONCLUSIONS: DFO increases erythroid precursor proliferation and has a synergistic in vivo effect with r-HuEpo in patients with chronic renal failure. Further investigations are needed to evaluate whether such an effect may have clinical application.