41Ca and Accelerator Mass Spectrometry to Monitor Calcium Metabolism in End Stage Renal Disease Patients

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Abstract
Background: Monitoring bone resorption with measurements of bone density and biochemical markers is indirect. We hypothesized that bone resorption can be studied directly by serial measurements of the ratio 41Ca/Ca in serum after in vivo labeling of calcium pools with 41Ca. We report the preparation of an intravenous 41Ca dose suitable for humans, an analytical method for determining 41Ca/Ca isotope ratios in biological samples, and studies in human volunteers. Methods: 41Ca was formulated and aliquoted into individual vials, and to the extent possible, the 41Ca doses were tested according to US Pharmacopeia (USP) guidelines. A 10 nCi dose of 41Ca was administered intravenously to 4 end stage renal disease (ESRD) patients on hemodialysis and 4 healthy control individuals. Distribution kinetics were determined over 168 days. Calcium was isolated with 3 precipitation steps and a cation-exchange column, and 41Ca/Ca ratios in serum were then measured by accelerator mass spectrometry. Results: The dosing solution was chemically and radiologically pure, contained <0.1 endotoxin unit/mL, and passed USP sterility tests. Quantification of 41Ca/Ca ratios was linear from 6 × 10−14 to 9.1 × 10−10. The run-to-run imprecision (as CV) of the method was 4% at 4.6 × 10−11 and 6% at 9.1 × 10−10. The area under the curve of 41Ca in the central compartment vs time was significantly less for ESRD patients than for controls (P <0.005). Conclusions: Isotope ratios spanning 5 orders of magnitude can be measured by accelerator mass spectrometry with excellent precision in the range observed in samples collected from patients who have received 10 nCi of 41Ca. The 41Ca at this dose caused no adverse effects in 8 volunteers. This is the first report of the use of 41Ca to monitor differences in bone turnover between healthy individuals and ESRD patients.