Effect of deferiprone, an oral iron chelator, in diabetic and non-diabetic glomerular disease.

Compelling experimental evidence exists for the role of oxidants and iron in glomerular disease. In preliminary studies, we confirmed increased urinary catalytic iron in patients with glomerulonephritis and diabetic nephropathy. We conducted two separate single-center, prospective, single-armed, open-labeled, proof-of-concept studies to evaluate the safety and efficacy of an oral iron chelator in patients with glomerulonephritis and diabetic nephropathy. Study 1 comprised 15 patients with biopsy-proven glomerulonephritis who had persistent proteinuria despite treatment with steroids and/or cyclophosphamides. Study 2 comprised 38 adult patients with diabetic nephropathy. Patients in Study 1 were treated with deferiprone (50 mg/kg/day) in three divided doses for 6 months and Study 2 patients were treated for 9 months. In Study 1, two patients had severe gastrointestinal intolerance and withdrew from the study after one dose and are not included in the results. There was a significant reduction (47 ± 9% mean) in 24-h urinary protein (4.01 ± 1.61 to 2.21 ± 1.62 [p = 0.009]), with no significant changes in serum creatinine. In Study 2, treatment with deferiprone resulted in a marked, persistent drop in the mean albumin/creatinine ratio (187 ± 47 at baseline to 25 ± 7 mg/g, [p = 0.01]) and stable renal function over a 9-month period. No clinically significant adverse events were observed in either study. Although these are small, open-labeled, and non-randomized studies, our results suggest that future randomized, double-blind trials examining the utility of deferiprone to treat glomerular diseases appear warranted.

Role of iron in atherosclerosis.

The importance of iron in injury is derived from the ease with which iron is reversibly oxidized and reduced and thus able to participate in the generation of powerful oxidant species, such as hydroxyl radical, and in lipid peroxidation. There is compelling mechanistic evidence for the potential role of iron in atherosclerosis: the role of iron in oxidizing low-density lipoprotein (LDL), iron chelators prevent endothelial cell damage by oxidized LDL, the ability of iron to cause endothelial cell damage, and iron chelators prevent endothelial cell dysfunction and vascular smooth muscle proliferation. In addition to these effects, important in atherosclerosis, ample experimental evidence suggests a role of iron in myocardial reperfusion injury. Epidemiological data have provided conflicting results, with several studies reporting an association between iron stores and progression of carotid atherosclerosis or acute myocardial infarction, whereas others argue against such an association. However, the availability of catalytic iron and the susceptibility of an individual may be more important than overall iron body status. Studies that address these issues, as well as those designed to establish cause and effect, are needed before one can reach meaningful conclusions about the role of iron in atherosclerosis and the therapeutic implications for patients.