Prevention and treatment of aluminum toxicity including chelation therapy: status and research needs

Abstract

The prevention and treatment of aluminum (Al) accumulation and toxicity are reviewed. Recommendations to further our understanding of desferrioxamine (deferoxamine, DFO) treatment and to develop more effective chelation approaches are provided. Reduction of Al accumulation and toxicity may benefit end-stage renal disease (ESRD) patients and perhaps those suffering from specific neurodegenerative disorders as well as workers with Al-induced neurocognitive disorders. The clearance of Al may be increased by extracorporeal chelation, renal transplantation, perhaps complexation with simple ligands such as silicon (Si), and systemic chelation therapy. The abilities of extracorporeal chelation and Si to reduce Al accumulation require further evaluation. Although it may not be possible to design Al-specific chelators, chelators with greater Al selectivity are desired. Aluminum-selective chelation might be achieved by targeted chelator distribution or by the use of adjuvants with the chelator. The ability of carboxylic acids to facilitate Al elimination, under specific conditions, warrants further study. Desferrioxamine does not produce significant biliary Al excretion. A chelator with this property may be useful in ESRD patients. The necessity for an Al chelator to distribute extravascularly to be effective is unknown and should be determined to guide the selection of alternatives to DFO. The lack of oral efficacy and occasional side effects of DFO encourage identification of orally effective, safer Al chelators. The bidentate 3-hydroxypyridin-4-ones are currently the most encouraging alternatives to DFO. They have been shown to increase urinary Al excretion in rats and rabbits, but to have toxicity comparable to, or greater than, DFO. Their toxicity may relate to incomplete metal complexation. The ability of orally effective chelators to increase absorption of chelated metal from the gastrointestinal (Gl) tract needs to be evaluated. Orally effective, safe Al chelators would be of benefit to peritoneal dialysis patients and those with neurodegenerative disorders, if Al chelation therapy is indicated. The reduction of Alzheimer's disease (AD) progression and the reversal of Al-induced behavioral deficits and neurofibrillary tangles by DFO encourage further study of Al chelation therapy for selected neurodegenerative disorders.