Limitations of conventional phosphate binders have led to the development of novel non-calcium, non-aluminium agents for use in patients with chronic kidney disease (CKD). The iron-based agent PA21 (stabilized polynuclear iron(III)-oxyhydroxide) has high phosphate binding capacity in vitro. This study was undertaken to investigate the uptake of iron after oral administration of PA21 in order to identify any potential risk of iron overload in the clinical setting, and to obtain a preliminary assessment of the effect of PA21 on serum phosphate levels prior to larger trials over a longer treatment period. An open-label, Phase I study was undertaken in which PA21 10 g/day was administered for 7 days to 8 nondialysis-dependent CKD patients (Stages 3 - 4), 8 maintenance hemodialysis patients and 8 healthy subjects. In addition, a single dose of radiolabeled PA21 was administered to determine iron uptake. Median iron uptake (range) was 0.06% (0.008 - 0.44%), 0.02% (0 - 0.04%) and 0.43% (0.16% - 1.25%) in the nondialysis-dependent CKD patients, hemodialysis patients and healthy subjects, respectively. Serum phosphate level decreased over the 7-day treatment period in the nondialysis patients (1.44 + or - 0.29 mmol/l to 1.10 + or - 0.27 mmol/l, p < 0.01) and the hemodialysis patients (2.85 + or - 0.78 mmol/l to 2.25 + or - 0.85 mmol/, p < 0.01). The most common adverse event was diarrhea (n = 9); all cases were mild to moderate. Findings from this short-term study indicate that PA21 may be an efficacious and well-tolerated phosphate binder with low iron uptake that may offer a promising alternative to existing hyperphosphatemia therapies. These results will need to be confirmed with longer-term, controlled studies.