Chronic renal failure is associated with increased tissue deposition of lanthanum after 28-day oral administration

Abstract

Background: Lanthanum (La) carbonate has recently been proposed as an alternative, calcium- and aluminum-free phosphate binder for the treatment of hyperphosphatemia of chronic renal failure (CRF). However, the extent to which CRF enhances tissue La accumulation induced by oral La overload above that observed under conditions of normal renal function remains a matter of debate. In the present study, we examined this issue in two different rat models of CRF.

Methods: In a first series of experiments, adult male Sprague-Dawley rats received either a diet to which 0.3% adenine (wt% in feed) was added to induce CRF ("chemical CRF,"N= 20), or a diet free of adenine (control, N= 16). In a second series of experiments, adult male Sprague-Dawley rats underwent 5/6 nephrectomy in a two-step procedure ("surgical CRF,"N= 24). Half of all CRF and control rats were exposed to dietary La (3% lanthanum carbonate, wt% in feed) for four weeks (La[+] rats), whereas the other half received a placebo (La[-] rats).

Results: At the end of this time period, creatinine clearance was 1.51 +/- 0.15 (mean +/- SEM) and 1.45 +/- 0.11 mL/min in La[-] control and La[+] control rats, and declined to 0.22 +/- 0.03 and 0.31 +/- 0.03 mL/min in La[+]-adenine-CRF and La[+]-Nx-CRF rats, respectively. Urinary La excretion was 0.025 +/- 0.010 microg/24 hr in La[-] control rats. It increased to 4.9 +/- 1.2, 17 +/- 3.8, and 77 +/- 18 microg/24 hr in La[+] control, La[+]-adenine-CRF, and La[+]-Nx-CRF rats, respectively. However, only the last value was significantly different from control value. Tissue La concentration was increased in La[+] control rats compared with La[-] control rats. More importantly, tissue La concentration was strikingly higher in La[+]-CRF rats than in La[+] control rats. Thus, liver La (ng/g dry wt) was 1173 +/- 148 in La[+]-adenine-CRF and 1742 +/- 158 in La[+]-Nx-CRF rats, respectively, compared with 385 +/- 29 in La[+] control rats (P < 0.001), and 7.0 +/- 1.4 in La[-] control rats; similarly, bone La was 230 +/- 14 and 288 +/- 26 compared with 81 +/- 8, respectively (P < 0.001), versus 27 +/- 4 in La[-] control rats. Comparable differences were observed in the kidney, skeletal muscle, myocardium, lung, and brain, although to different extents in La[+]-adenine-CRF compared with La[+]-Nx-CRF rats. Finally, liver and kidney weight was significantly reduced in La[+]-adenine-CRF rats compared with La[-]-adenine-CRF rats.

Conclusion: The oral administration of lanthanum carbonate to normal rats leads to a more than 10-fold increase of tissue La content in at least some organs, including the liver, lung, and kidney. This increase is further enhanced by the uremic state, per se. Plasma levels are a poor indicator of tissue burden. Given the dramatic tissue levels obtained with this rare earth metal given by the oral route, particularly in liver for absolute values, it is probable that the stimulation by CRF is at least partially explained by an increase in intestinal La absorption. The absorptive pathways involved in intestinal La absorption require further study, including possibly enhancing conditions.