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Veerle P. Persy, Geert J. Behets, An R. Bervoets, Marc E. De Broe, and Patrick C. D’HaeseUniversity of Antwerp, Antwerp, Belgium ABSTRACT
Accumulation of inorganic phosphate due to renal functional and its effects in bone, liver and brain are discussed. Although impairment contributes to the increased cardiovascular mortal- lanthanum is a metal cation its effects are not comparable to ity observed in dialysis patients. Phosphate plays a causative those of aluminum. Indeed, in clinical studies no toxic effects role in the development of vascular calcification in renal fail- of lanthanum have been reported after up to four years of fol- ure; treatment with calcium-based phosphate binders and vita- low-up. The bioavailability of lanthanum is extremely low. The min D can further increase the Ca × PO product and add to the effects observed in bone are due to phosphate depletion, with risk of ectopic mineralization. The new generation of calcium- no signs of direct bone toxicity yet observed in rats or humans.
free phosphate binders, sevelamer and lanthanum, can control The liver is the main route of excretion for lanthanum carbon- hyperphosphatemia without adding to the patients calcium ate, which can be localized in the lysosomes of hepatocytes. No load. In this article, the metabolism of lanthanum carbonate lanthanum could be detected in brain tissue.
Inorganic phosphate plays a role in important cellular The disturbed mineral metabolism that accompanies functions such as energy storage and signaling, and in chronic renal failure contributes to the development of bone mineralization. Loss of renal function limits phos- ectopic calcification. Vascular calcification is a promi- phate excretory capacity and causes an increase in serum nent feature of cardiovascular disease in uremic patients.
phosphate level, which together with low ionized cal- In a landmark article, Goodman et al. (7) showed that cium levels, contributes to the development of secondary coronary artery calcification is already present in young hyperparathyroidism and renal osteodystrophy (ROD).
hemodialysis patients, shows rapid progression, and is In the long run, these factors cause parathyroid gland associated with increased serum phosphate and calcium- hyperplasia and autonomous parathyroid hormone (PTH) phosphate product. Vascular calcification in dialysis production (tertiary hyperparathyroidism) (1,2).
patients is associated with a higher daily calcium intake Phosphate accumulation in the body and hyperphos- from calcium-based phosphate binders (7–9). Hence phatemia are associated with an increased mortality risk.
attempts to control serum PTH levels with calcium- In hemodialysis patients, serum phosphate levels greater based phosphate binders and vitamin D supplements can than 6.5 mg /dl, as well as elevated calcium-phosphate further increase the calcium-phosphate product and the product (greater than 72 mg2/dl2) are associated with a risk for ectopic calcification and its associated cardio- significantly increased mortality risk (3). In patients with vascular mortality. In addition to increased calcification chronic kidney disease (CKD), there is a linear increase of atherosclerotic plaques in the vessel (neo)intima, in mortality as serum phosphate rises above 3.5 mg /dl, a patients on dialysis also show characteristic calcifica- level that is still in the normal range (4). Phosphate reten- tions of the vascular media (arteriosclerosis or Möncke- tion mainly increases cardiovascular mortality, such as berg sclerosis), which were recently shown to also death through coronary artery disease and sudden death contribute significantly to the excess cardiovascular mor- (5). Physiologic phosphate homeostasis is controlled by tality observed in uremic patients (8).
a number of phosphaturic factors in addition to PTH, In vitro studies have elegantly demonstrated that ele- such as FGF-23 and the so-called phosphatonins, while vated phosphate and calcium levels are causative players no phosphate retention-inducing factors have been iden- in the cell-mediated process of uremia-related calcifica- tified so far. Overall, studies indicate that accumulation tion of the vascular tunica media (10). In cultured human of phosphate and concomitant hyperphosphatemia form aortic smooth muscle cells, a dose-dependent increase in a serious threat to survival in CKD (6).
mineral deposition was observed, together with loss ofsmooth muscle cell differentiation markers and conver-sion of smooth muscle cells to an osteogenic phenotype, Address correspondence to : Veerle P. Persy, MD, PhD, characterized by expression of the osteoblast transcrip- University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, tion factor cbfa-1 and the osteoblast protein osteocalcin Antwerp, Belgium, or e-mail:
(11,12). These effects could be inhibited by blocking Seminars in Dialysis—Vol 19, No 3 (May–June) 2006 phosphate entrance into the cell through the sodium/ phosphorus cotransporter Pit-1 with phosphonoformic Fig. 1. Metabolism of two trivalent cations: aluminum and lanthanum. In contrast to aluminum, there is no increased deposition of lanthanum in end-stage renal disease compared to patients with normal renal function. Adapted from Behets et al. (23).
acid (11). In epigastric arteries of uremic patients under- biological ligands are the carboxyl and phosphate groups going transplantation, the presence of calcification was ( PO3−) with which it can form very tight complexes.
associated with expression of cbfa-1 (13), alkaline phos- In comparison with aluminum, lanthanum accumu- phatase, and the bone matrix proteins osteopontin, bone lates to a lesser extent in the body of dialysis patients, sialoprotein, and collagen type I (14), confirming the mainly because of its ultralow gastrointestinal absorp- cell biological parallels between vascular calcification tion and biliary elimination of the small absorbed and bone formation. Several proteins possessing a high fraction (Fig. 1). Studies have shown that the absolute calcium affinity, such as matrix Gla protein, osteoprote- bioavailability of lanthanum in man is less than 0.002%, grin, osteopontin, and fetuin, may modulate the ectopic with the majority of an oral dose being excreted in the calcification process in the vasculature by their ability to feces. Biliary elimination (80%) and direct transport act as natural inhibitors of these calcifications.
across the gut wall into the lumen (13%) represent the The available calcium-free phosphate binders include main routes of elimination. Therefore the elimination sevelamer hydrochloride (a nonaluminum, noncalcium- of lanthanum is not dependent on renal function; of a containing hydrogel of cross-linked poly(allylamine lanthanum dose of 1 g/day in healthy volunteers, only hydrochloride) that binds phosphate anions through 0.00003% was excreted in the urine (19), indicating that, ionic exchange with chloride) and more recently, lantha- compared with individuals with normal renal function, num carbonate. These products can control phosphate chronic renal insufficiency patients are not at an levels without inducing calcium overload. In comparison increased risk for accumulation of the element. This has with calcium-based phosphate binder therapy, treatment been confirmed in several phase 1 clinical studies, which with sevelamer slowed down the progression of coronary have indicated similar plasma exposure and pharmaco- artery and aortic calcification in dialysis patients (15,16).
kinetics of lanthanum in dialysis patients and healthy However, apart from its phosphate binding activity, seve- lamer also acts as a bile acid sequestrant (17), resulting This is in contrast to orally administered aluminum, of in lowering of total and low-density lipoprotein (LDL) which 0.01– 0.10% is absorbed from the gastrointestinal cholesterol, and can induce acidosis by exchange of tract (Fig. 1) (20,21), and which is mainly eliminated via bicarbonate with chloride ions (18). These additional the kidney, biliary excretion being negligible. When effects can also influence the calcification process. How- calcium citrate was coadministered with aluminum hydro- ever, no studies on the effect of lanthanum carbonate, xide (2.4 g/day), aluminum excretion increased from 70 – which is a pure phosphate binder, on vascular calcifica- 120 mg/day up to 350 – 603 mg/day (21). Citrate does not tion in dialysis patients are available yet.
influence gastrointestinal absorption of lanthanum.
Lanthanum belongs to the group of elements known as the “lanthanides.” It is the most electropositive (cationic)element of the rare earth group, is uniformly trivalent, and its binding is almost exclusively ionic. It is ahard “acceptor” with an overwhelming preference for In experimental studies, no effects of lanthanum on oxygen-containing anions. Therefore the most common bone have been observed in animals with normal renal bone calcium, knowledge of the molar bone cation:calcium ratio is of particular interest for a better under-standing of its potential to disrupt bone mineral struc-ture. Regarding lanthanum (molecular weight 139), thehighest concentration observed in the bone of dialysispatients was 9.5 µg/g (67 nmol/g) wet weight after 4.5years of treatment with lanthanum carbonate (2.5 –3.0 g /day). Considering a bone calcium concentration of 120mg /g (3 mmol/g) and assuming a homogeneous distribu-tion of lanthanum throughout the bone, the molar bonelanthanum:calcium ratio would be as low as 2 × 10−5,that is, only 1 out of 50,000 calcium atoms would bereplaced by lanthanum. If one assumes lanthanum toaccumulate in only 1% of the total bone volume, stillonly 1 out of 500 calcium ions would be replaced bylanthanum, and any effect on either bone mineral crystalnucleation, crystal growth, or structure would not readilybe expected. Applying the same reasoning to aluminumand assuming the total amount of the element (up to50 µg/g, 1.8 µmol/g) is localized in only 1% of the total Fig. 2. Using the highly sensitive methodology of X-ray fluore- bone volume (a reasonable assumption in patients with scence, lanthanum was found at several sites in human bone.
aluminum-related osteomalacia in which the element islocalized at the osteoid-calcification front of the bone), function loaded with lanthanum at doses up to 2000 mg / the molar bone aluminum:calcium ratio would be kg /day for 2 years (22). On the other hand, rats with 6 × 10−2. In other words, 1 out of 16 calcium atoms chronic renal failure loaded with doses of 1000 –2000 would be replaced by aluminum, increasing the probabil- mg/kg/day for 12 weeks showed an impairment of bone ity of toxic effects at the level of apatite nucleation, crys- mineralization (23). However, several further studies produced evidence that the observed lesions were phar- A randomized, comparator-controlled, parallel-group, macologically mediated and resulted from phosphate open-label study was set up to assess the evolution of depletion induced by the administration of high doses of ROD in dialysis patients receiving treatment with lantha- lanthanum carbonate rather than being the consequence num carbonate versus calcium carbonate for 1 year, with of a direct toxic effect of the compound.
particular emphasis on the possible development of Further evidence of the absence of any direct toxicity aluminum-like bone diseases, that is, osteomalacia or of lanthanum on bone includes the fact that bone lantha- num concentration does not correlate with the various Paired bone biopsy specimens were taken in 63 histomorphometric bone parameters, and the effects of patients at the start and after 12 months of treatment with lanthanum on bone mimic those induced by feeding a low- either lanthanum carbonate (n = 33) or calcium carbon- phosphate diet, are normalized with phosphate repletion ate (n = 30). The bone biopsies were assessed for lan- (24), and are similar to those observed in rats treated thanum content, and were examined for histologic and with sevelamer (25). Moreover, whereas in dialysis patients with aluminum-related bone disease (expressed After 1 year of lanthanum carbonate treatment, serum either as osteomalacia or adynamic bone) aluminum lanthanum levels were slightly increased, although not accumulation was accompanied by a decreased number/ dose-dependently (mean serum levels ranging from 0.51 activity of osteoblasts (26), such an effect was not seen to 1.08 ng /ml), and reached a plateau within 12 weeks of after lanthanum loading in either rats or humans (27).
treatment. After 1 year of treatment with lanthanum car-bonate, bone lanthanum levels did not exceed 5.5 µg/gwet weight (median 1.8 µg/g).
The distribution of the different types of ROD at base- Studies in animals and humans have shown that lan- line was comparable between the two groups, with thanum is deposited in bone and liver. Localization of mixed ROD being the most common type. After 1 year of lanthanum in bone, obtained by means of X-ray fluorescence treatment, lanthanum carbonate was associated with a at the European Synchrotron Radiation Facility, Greno- reduction in each of the more extreme forms of ROD ble, France, showed the element to be present at both (i.e., hyperparathyroidism, adynamic bone disease, and active and quiescent sites of bone mineralization, inde- osteomalacia). Calcium carbonate was associated with pendent of the type of ROD, as well as diffusely distrib- an increase in the proportion of patients with hyper- uted throughout the mineralized bone matrix, especially parathyroidism or adynamic bone disease. Overall, five in rats and humans with increased bone turnover (Fig. 2).
out of seven (71%) lanthanum carbonate-treated patients Lanthanum was also found in cells in close proximity to with low-turnover bone disease (adynamic bone or the resorption lacunae (osteoclasts, macrophages) (28).
osteomalacia) at baseline, and 80% (four out of five) of As the accumulation of cations in bone goes along those with baseline hyperparathyroidism evolved toward with an interaction between the cation of interest and a normalization in bone turnover, compared with three Fig. 4. Lanthanum in a crystalline, granular-like form was found in the lysosomes (black arrows) of the hepatocytes. No lanthanum was Fig. 3. Liver enzymes after treatment with lanthanum carbonate or detected in other organelles such as mitochondria, nucleus, cytoplasm, or Golgi apparatus. Transmission electron microscopy of the liver tissueof lanthanum loaded rats. Rats were loaded with a very high dose of0.3 mg / kg /day intravenously over 4 weeks (31).
out of seven (42%) and three out of six (50%) calciumcarbonate-treated patients, respectively.
In summary, the proportion of patients with adynamic bone disease, osteomalacia, or hyperparathyroidism in For the energy dispersive X-ray (EDX) analytical the lanthanum carbonate group decreased from 36% to work, an atmospheric thin window Oxford instrument 18% after 1 year of treatment, whereas the number of was connected to a CM20 TEM instrument equipped patients with these types of ROD increased from 43% to with a lanthanum hexaboride (LaB ) single crystal fila- 53% in the calcium carbonate group. In the lanthanum ment operating at 200 kV, 120 kV, or 80 kV. For the elec- group, no aluminum-like effects on bone were observed.
tron energy loss spectroscopy (EELS), a postcolumnGIF2000 instrument was used in connection with anUltratwin CM30 TEM instrument equipped with a field emission gun (FEG) and operating at 300 kV. The com-bined use of these techniques indicated lanthanum to be Since the liver is the main excretory organ of lantha- present in the lysosomes of the hepatocytes (Fig. 4). No num, it is not surprising to find some deposition of the lanthanum was detected in mitochondria, the nucleus, or element at this site. However, clinical studies with up to cytoplasm. Furthermore, most of the lanthanum was 4 years of follow-up have not disclosed any hepatotoxic found in lysosomes at the biliary pole of the hepatocyte effect of the drug in patients treated with this phosphate and within the bile canaliculus (30).
binder (Fig. 3). Twelve weeks of lanthanum loading byoral gavage of 2000 mg/kg/day to rats with moderaterenal failure resulted in concentrations of 1.5 µg/g and 3.5 µg/g of lanthanum in bone and liver, respectively.
Brain levels remained below the detection limit. Other In a number of experimental studies, lanthanum was tissues such as heart, skin, and lung showed no tissue determined to be in several regions of the brain after administration of intravenous doses of 30–300 mg/kg/ In order to identify the localization of lanthanum in day over 4 weeks and oral gavage of 1500 mg/kg/day. No the liver, lanthanum chloride was administered by daily lanthanum could be detected (less than 6 ng/g).
intravenous injection to rats with normal renal functionat a 0.3 mg/kg dose over 4 weeks. The total liver lantha-num concentrations varied between 30 and 50 µg/g.
Liver fragments of treated as well as untreated animals were fixed in 4% formaldehyde in phosphate buffer and Lanthanum carbonate is an effective aluminum- and postfixed in reduced osmium tetroxide (OsO ). After calcium-free phosphate binder. The drug is well tolerated dehydration and embedding in Epon, 100 nm, 500 nm, and the reported incidence of gastrointestinal side effects and 1000 nm sections were prepared. These were exam- is comparable with reports on calcium-containing phos- ined by conventional imaging in a Zeiss transmission electron microscope (TEM) at 50 kV or a Philips TEM Available bone biopsy data in dialysis patients treated (at 80 kV) either without or after counterstaining with for up to 4 years with lanthanum carbonate indicate low- lead citrate, at magnifications varying between 1800× level bone deposition, the highest concentration ever measured in any patient being 9.4 µg/g. Ultrastructural localization indicates a heterogeneous distribution of 12. Giachelli CM: Ectopic calcification: new concepts in cellular regulation. Z lanthanum in the bone of rats and man. The low molar 13. Moe SM, Duan D, Doehle BP, O’Neill KD, Chen NX: Uremia induces the lanthanum:calcium ratio is unlikely to cause physico- osteoblast differentiation factor Cbfa1 in human blood vessels. Kidney Int chemical interactions of the metal with hydroxyapatite 14. Moe SM, O’Neill KD, Duan D, Ahmed S, Chen NX, Leapman SB, Fineberg development and structure. Furthermore, no adverse cell N, Kopecky K: Medial artery calcification in ESRD patients is associated biological effects of lanthanum on osteoblasts have been with deposition of bone matrix proteins. Kidney Int 61:638 – 647, 2002 15. Chertow GM, Burke SK, Raggi P: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int The presence of lanthanum in the bile and in the lyso- somes of the liver is consistent with excretion of lanthanum 16. Block GA, Spiegel DM, Ehrlich J, Mehta R, Lindbergh J, Dreisbach A, by the liver via the transferrin receptor-endosomal- Raggi P: Effects of sevelamer and calcium on coronary artery calcification inpatients new to hemodialysis. Kidney Int 68:1815 –1824, 2005 lysosomal-bile canaliculus pathway. Clinical studies of 17. Braunlin W, Zhorov E, Guo A, Apruzzese W, Xu Q, Hook P, Smisek DL, up to 4 years have not disclosed any hepatotoxic effect of Mandeville WH, Holmes-Farley SR: Bile acid binding to sevelamer HCl.
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