Safety issues of iron chelation therapy in patients with normal range iron stores including thalassaemia, neurodegenerative, renal and infectious diseases.

An increased number of thalassaemia patients treated with effective chelation therapy protocols are achieving body iron levels similar to those of normal individuals. Iron chelation therapy has also been recently used in a number of other categories of patients with no excess body iron load such as neurodegenerative, renal and infectious diseases. Chelation therapy in the absence of iron overload in the latter conditions raises many safety issues including chelator overdose toxicity and toxicity related to iron and other essential metal deficiencies. Preliminary preclinical and clinical toxicity evidence suggest that deferoxamine and deferasirox can only be safely used for these non-iron loaded conditions for short-term treatments of a few weeks, whereas deferiprone can be used for longer term treatments of many months. The selection of the chelating drug and appropriate dose protocols for targeting specific organs and conditions is critical for the safety of patients with normal iron stores. Chelation therapy is likely to play a major role as adjuvant, alternative or main therapy in many non-iron loading conditions in the forthcoming years.

Effect of selenium-deficient diet in experimental glomerular disease.

We examined the effect of a selenium-deficient diet on two experimental models of glomerular disease, the puromycin aminonucleoside (PAN)-induced nephrotic syndrome, a model of minimal change disease, and passive Heymann nephritis, a complement-dependent and neutrophil-independent model that resembles membranous nephropathy. The specific activity of selenium-dependent glutathione peroxidase was markedly reduced in the liver, the kidney cortex, and in glomeruli in weanling male Sprague-Dawley rats placed on a selenium-deficient diet for 6 wk compared with rats fed a selenium-replete diet, with no significant differences in the specific activities of superoxide dismutase or catalase. PAN-injected selenium-deficient rats had a marked and significantly greater proteinuria throughout the course of the experiment compared with PAN-injected selenium-replete rats with no significant histological differences. In the passive Heymann nephritis model induced by injecting anti-Fx1A immunoglobulin G, rats fed a selenium-deficient diet had significantly higher urinary protein (day 5: 91 +/- 16 mg/24 h, n = 10) compared with rats fed a selenium-replete diet (52 +/- 5 mg/24 h, n = 11) with no differences in the amount of antibody deposited in the kidney. The most likely explanation for the effect of a selenium-deficient diet is that selenium deficiency resulted in a marked reduction of glutathione peroxidase, thus indicating an important role of glutathione peroxidase in these models of glomerular injury.

Renal brush border membrane adaptation to phosphorus deprivation: effects of fasting versus low-phosphorus diet.

Alimentary phosphorus deprivation due to a low-phosphorus diet (LPD) elicits a profound antiphosphaturia and an increase in sodium-dependent inorganic phosphate (Pi) uptake by renal cortical brush border membrane (BBM) vesicles. But, in alimentary phosphorus deprivation due to total fasting, high urinary excretion of Pi persists. In the present study, we determined whether low tubular reabsorption of Pi in fasting is due to a diminished capacity of the specific Pi transport system with the renal cortical luminal BBM or whether it is due to a reduced transepithelial reabsorption of Pi because of metabolic conditions occurring in proximal tubule cells during fasting. Sodium-dependent Pi transport in compared with fasted rats or rats fed a normal phosphorus diet. Sodium-dependent uptake of D-glucose was significantly lower in LPD rats, compared with fast animals or animals fed a normal diet. Thus, in contrast to LPD, fasting does nt elicit an increase in Pi transport and a decrease in D-glucose transport across the isolated renal BBM. The same differences in BBM transport of Pi were present also in thyroparathyroidectomized rats. Further experiments demonstrated that the adaptation of renal function and the renal BBM transport to LPD are overridden by a subsequent period of total fasting. Results of the present study show that fasting both prevents and reverses the renal response of rats to alimentary phosphorus deprivation. The differences in Pi excretion between fasted rats, LPD rats, and LPD rats subsequently fasted are attributed, at least in part, to specific adaptive changes in sodium-dependent Pi transport across the luminal BBM, rather than to alterations in other cellular (metabolic) components of transepithelial Pi reabsorption in the proximal tubule.