Hepatocellular transport and gastrointestinal absorption of lanthanum in chronic renal failure.

Lanthanum carbonate is a new phosphate binder that is poorly absorbed from the gastrointestinal tract and eliminated largely by the liver. After oral treatment, we and others had noticed 2-3 fold higher lanthanum levels in the livers of rats with chronic renal failure compared to rats with normal renal function. Here we studied the kinetics and tissue distribution, absorption, and subcellular localization of lanthanum in the liver using transmission electron microscopy, electron energy loss spectrometry, and X-ray fluorescence. We found that in the liver lanthanum was located in lysosomes and in the biliary canal but not in any other cellular organelles. This suggests that lanthanum is transported and eliminated by the liver via a transcellular, endosomal-lysosomal-biliary canicular transport route. Feeding rats with chronic renal failure orally with lanthanum resulted in a doubling of the liver levels compared to rats with normal renal function, but the serum levels were similar in both animal groups. These levels plateaued after 6 weeks at a concentration below 3 microg/g in both groups. When lanthanum was administered intravenously, thereby bypassing the gastrointestinal tract-portal vein pathway, no difference in liver levels was found between rats with and without renal failure. This suggests that there is an increased gastrointestinal permeability or absorption of oral lanthanum in uremia. Lanthanum levels in the brain and heart fluctuated near its detection limit with long-term treatment (20 weeks) having no effect on organ weight, liver enzyme activities, or liver histology. We suggest that the kinetics of lanthanum in the liver are consistent with a transcellular transport pathway, with higher levels in the liver of uremic rats due to higher intestinal absorption.

Development and reversibility of impaired mineralization associated with lanthanum carbonate treatment in chronic renal failure rats.

BACKGROUND: We have previously shown that administration of the new phosphate binder lanthanum (La) carbonate at high doses during 12 weeks induces a mineralization defect (MD) in chronic renal failure (CRF) rats most likely due to the powerful phosphate binding. In this study, we want to investigate the fate and possible biological activities of La once it is accumulated in bone. METHODS: CRF animals (5/6th nephrectomy) received La carbonate (2,000 mg/kg/day) via oral gavage for 2 or 6 weeks and were sacrificed immediately at the end of the treatment period and after a wash out period of 2 and 8 weeks. Bone histomorphometry and measurement of bone La content were performed. Control CRF animals received vehicle only. RESULTS: After 2 weeks of La treatment, 75% of the animals showed signs of MD compared to 14% in CRF controls despite similar bone La levels. Two weeks after arrest of La treatment, bone La levels remained unchanged, yet 87% showed normal bone histology. A similar evolution was noted in the animals treated for 6 weeks. Bone histology showed a reduction of number of animals with a MD from 62.5% at 6 weeks of La treatment to 20% and 28% 2 and 8 weeks after arrest of La treatment respectively. CONCLUSION: The phosphate-binder-induced MD may appear and disappear without any change in either the perimeter of active osteoblasts or in bone La levels. Bone histology in CRF animals normalized after arrest of the La administration, thereby presenting further arguments for the MD in La-treated animals to result from the high phosphate binding capacity of La rather than being the consequence of a direct effect of La on bone.

Useful biochemical markers for diagnosing renal osteodystrophy in predialysis end-stage renal failure patients.

BACKGROUND: Various biochemical markers have been evaluated in dialysis patients for the diagnosis of renal osteodystrophy (ROD). However, their value in predialysis patients with end-stage renal failure (ESRF) is not yet clear. METHODS: Bone histomorphometric evaluation was performed and biochemical markers of bone turnover were determined in serum of an unselected predialysis ESRF population (N = 84). RESULTS: Significant (P < 0.005) differences between the five groups with ROD (ie, normal bone [N = 32], adynamic bone [ABD; N = 19], hyperparathyroidism [N = 8], osteomalacia [OM; N = 10], and mixed lesion [N = 15]) were noted for intact parathyroid hormone, total (TAP) and bone alkaline phosphatase (BAP), osteocalcin (OC), and serum calcium levels. Serum creatinine and (deoxy)pyridinoline levels did not differ between groups. For the diagnosis of ABD, an OC level of 41 microg/L or less (< or =7.0 nmol/L) had a sensitivity of 83% and specificity of 67%. The positive predictive value (PPV) for the population under study was 47%. The combination of an OC level of 41 ng/L or less (< or =7.0 nmol/L) with a BAP level of 23 U/L or less increased the sensitivity, specificity, and PPV to 72%, 89%, and 77%, respectively. ABD and normal bone taken as one group could be detected best by a BAP level of 25 U/L or less and TAP level of 84 U/L or less, showing sensitivities of 72% and 88% and specificities of 76% and 60%, corresponding with PPVs of 89% and 85%, respectively. In the absence of aluminum or strontium exposure, serum calcium level was found to be a useful index for the diagnosis of OM. CONCLUSION: OC, TAP, BAP, and serum calcium levels are useful in the diagnosis of ABD, normal bone, and OM in predialysis patients with ESRF.

Spectrum of renal bone disease in end-stage renal failure patients not yet on dialysis.

BACKGROUND: During the last few years the spectrum of renal osteodystrophy (ROD) in dialysis patients has been studied thoroughly and the prevalence of the various types of ROD has changed considerably. Whereas until a decade ago most patients presented with secondary hyperparathyroidism (HPTH), adynamic bone (ABD) has become the most common lesion within the dialysis population over the last few years. Much less is known about the spectrum of ROD in end-stage renal failure (ESRF) patients not yet on dialysis. METHODS: Transiliac bone biopsies were taken in an unselected group of 84 ESRF patients (44 male, age 54+/-12 years) before enrolment in a dialysis programme. All patients were recruited within a time period of 10 months from various centres (n=18) in Macedonia. Calcium carbonate was the only prescribed medication in patients followed up by the outpatient clinic. RESULTS: HPTH was found in only 9% of the patients, whilst ABD appeared to be the most frequent renal bone disease as it was observed in 23% of the cases next to normal bone (38%). A relatively high number of patients (n=10; 12%) fulfilled the criteria of osteomalacia (OM). Mixed osteodystrophy (MX) was diagnosed in 18% of the subjects. There was no significant difference between groups in age, creatinine, or serum and bone strontium and aluminium levels. Patient characteristics associated with ABD included male gender and diabetes, whilst OM was associated with older age (>58 years). CONCLUSIONS: In an unselected population of ESRF patients already, 62% of them have an abnormal bone histology. ABD is the most prevalent type of ROD in this population. In the absence of aluminium or strontium accumulation the relatively high prevalence of a low bone turnover as expressed by either normal bone or ABD and OM is striking.