Hepatocellular transport and gastrointestinal absorption of lanthanum in chronic renal failure

Abstract

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.

Tissue Accumulation of Lanthanum as Compared to Aluminum in Rats with Chronic Renal Failure – Possible Harmful Effects after Long-Term Exposure

“…The results of these studies were compatible with an increase by the uremic state of intestinal absorption and tissue deposition of La in various organs after either short-term (4 weeks) or long-term (up to 20 weeks) exposure to oral La carbonate [13,14,22]. In addition, in the study by Lacour et al [13] there was a hint to potential liver toxicity because of a concomitant decrease of liver weight in one of the two experimental CRF models used, namely the adenine model [13].…”

“…No gross changes of liver structure were noted in any rat group after 12 weeks of observation, like in the study by Ben-Dov et al [25] and Bervoets et al [22]. Hepatocyte size was comparable between either La- or Al-overloaded animals and control animals.…”

“…The reason for our focus on the liver was that after the initial barrier of the intestinal wall this organ represents the second most important filter for ingested compounds. Since the uremic state is probably associated with enhanced absorption of La from the gut lumen and deposition in the liver [13,22], similarly to that reported for Al [26,27], it is not surprising that La deposition is 3- to 30-fold higher in the liver than in bone or brain [13]. …”

“…These findings stimulated discussion on potential La toxicity and led to further studies on the distribution of retained La at the cellular and subcellular level both in rats [15,23] and in patients [16]. The finding of large amounts of La in hepatic lysosomes and bile canaliculae of rats, but not in hepatic mitochondria, nuclei, or cytoplasm as reported by Yang et al [24] and more recently by Bervoets et al [22], led the authors to speculate that this storage system protected the liver tissue and extrahepatic tissues from toxic effects, directing the trace element directly to the bile excretory tract. The authors used findings from repeat bone biopsy studies in chronic hemodialysis patients in whom La carbonate administration failed to reveal evidence for toxic changes of bone structure as indirect support for this theory [16].…”

The management of hyperphosphatemia by lanthanum carbonate in chronic kidney disease patients

“…In subsequent investigations, as lanthanum was a locally present lysosome in the liver and was excreted via bile, no hepatotoxicity was observed. 28,29 In addition, there was no liver toxicity in HD patients treated with lanthanum carbonate for 6 years' long-term follow-up. 18 …”