Incredulous effects of lanthanum?
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Animals↗
Biomedical subjects
Marc E De Broe
Publications and source records attributed to Marc E De Broe.
Evolution of bone and plasma concentration of lanthanum in dialysis patients before, during 1 year of treatment with lanthanum carbonate and after 2 years of follow-up.
BACKGROUND: Lanthanum carbonate (LC) has been proposed as a new phosphate binder. Presented here are the results from one centre that participated in a multicentre trial to assess the effect of treatment with LC and calcium carbonate (CC) on the evolution of renal osteodystrophy in dialysis patients. Bone biopsies were performed at baseline, after 1 year of treatment and after a further 2-year follow-up period to assess the lanthanum concentration in bone and plasma. METHODS: Twenty new dialysis patients were randomized to receive LC (median dose 1250 mg) for 1 year (n = 10), followed by 2 years of CC treatment or CC (n = 10) during the whole study period (3 years). RESULTS: After 36 weeks of treatment, steady state was reached with plasma lanthanum levels varying around 0.6 ng/ml. Six weeks after cessation of 1 year of treatment, the plasma lanthanum levels declined to a value of 0.17 +/- 0.12 ng/ml (P < 0.05) and after 2 years to 0.09 +/- 0.03 ng/ml. Plasma and bone lanthanum levels did not correlate with the average lanthanum dose at any time point. The mean bone concentration in patients receiving LC increased from 0.05 +/- 0.03 to 2.3 +/- 1.6 microg/g (P < 0.05) after 1 year and slightly decreased at the end of the study to 1.9 +/- 1.6 microg/g (P < 0.05). CONCLUSIONS: Bone deposition after 1 year of treatment with LC is low (highest concentration: 5.5 microg/g). There is a slow release of lanthanum from its bone deposits 2 years after the discontinuation of the treatment and no association with aluminium-like bone toxicity.
Aged↗
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.
Animals↗
Tubular regeneration and the role of bone marrow cells: 'stem cell therapy'--a panacea?
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Animals↗
Kidney injury from alternative medicines.
In the developing world, up to 80% of the population uses traditional medicine for primary health care. In industrialized countries, adaptations of traditional medicine, termed "complementary" or "alternative" medicine (CAM), are used by a growing number of patients for preventive or palliative care. However, alternative medicine (AM) may be an important risk for the development of acute and chronic kidney injury because of several factors: nonconventional preparations rarely meet the required essential standards of consistency in composition and biological activity; many of these products contain undisclosed over-the-counter or prescription drugs or can be adulterated with hormones and glandular extracts; herbal preparations can be contaminated by pesticides and heavy metals; and because of errors in plant identification and confusing terminology, opportunities for mistakes and deliberate substitution can occur. Furthermore, there is a lack of reports of adverse events and drug interactions because of a lack of professional surveillance, and specific data on systemic and kidney toxicity are not easily available. Kidney injury/kidney syndromes caused by AM consist of acute tubular necrosis/toxicity (eg, Fanconi's syndrome), acute interstitial nephritis, papillary necrosis, hypertension, kidney stones, urinary retention, chronic tubulointerstitial nephritis with fibrosis, urinary tract carcinoma, and acute rejection of the kidney transplant. To improve the care for patients using AM, extension of physicians' knowledge about its possible hazards and toxicity is essential. This review deals with acute and chronic kidney toxicity caused by animal-, plant-, and mineral-based, nonconventional medicine and kidney failure caused by drug interactions with AM.
Complementary Therapies↗
Time-evolution and reversibility of strontium-induced osteomalacia in chronic renal failure rats.
BACKGROUND: Patients with impaired renal function can accumulate strontium in the bone, which has been associated with the development of osteomalacia. A causal role for strontium in the development of the disease was presented in chronic renal failure (CRF) rats. Strontium-ranelate has been put forward as a therapeutic agent in the treatment of osteoporosis. Since the target population for strontium treatment consists mainly in postmenopausal osteoporotic women, who may have a reduced renal function, the risk for osteomalacia should be considered. METHODS: To determine the time evolution and reversibility of the strontium-induced mineralization defect, CRF rats were loaded with strontium (2 g/L) (+/- 200 mg/kg/day) during 2, 6, and 12 weeks, followed by a washout period of 0, 2, 4, or 8 weeks. RESULTS: Histologic examination of the bone of the animals treated with strontium revealed signs of osteomalacia already after 2 weeks. Animals that received strontium during 6 and 12 weeks had a significantly higher osteoid perimeter, area and thickness as compared to CRF controls. After 12 weeks, the mineralization was significantly affected, as evidenced by a lower double-labeled surface, mineral apposition and bone formation rate in combination with an increased osteoid maturation time and mineralization lag time. The osteoblast perimeter was significantly lower in the strontium-treated animals. After the washout periods, these effects were reversed and the bone lesions evolved to the values of CRF controls. This went along with an 18% reduction of the bone strontium content. A significant rise in serum alkaline phosphatase (ALP) activity was apparent in the strontium-treated animals as compared to CRF controls. This was not only due to higher levels of the bone ALP but also to those of the liver and the intestinal isoenzymes. Serum parathyroid hormone (PTH) levels decreased during strontium treatment. After cessation of the treatment, the serum ALP activity and PTH concentration reversed to control levels. CONCLUSION: In this study evidence is provided for the rapid development of a mineralization defect in strontium-loaded CRF rats, accompanied by a reduced osteoblast number, reduced PTH synthesis or secretion, and increased serum ALP levels. These effects can be rapidly reversed after withdrawal of the compound.
Alkaline Phosphatase↗
Localization of lanthanum in bone of chronic renal failure rats after oral dosing with lanthanum carbonate.
BACKGROUND: Lanthanum carbonate has been shown to be a safe, effective phosphate-binding agent. We have shown that an impaired mineralization in chronic renal failure rats treated with high doses of lanthanum carbonate develops secondary to phosphate depletion and is therefore pharmacologically mediated rather than a direct effect of lanthanum on bone. Although bulk bone lanthanum concentrations are low, it is important to consider the localization within a given tissue. METHODS: Using the scanning x-ray micro-fluorescence set-up at beamline ID21 of the European Synchrotron Radiation Facility, calcium and lanthanum distributions in bone samples were mapped. RESULTS: In chronic renal failure rats loaded orally with lanthanum carbonate (12 weeks) (2000 mg/kg/day), bulk bone lanthanum concentrations reached values up to 5 microg/g wet weight. Lanthanum could be demonstrated at the edge of the mineralized bone, at both actively mineralizing and quiescent sites, independent of the type of bone turnover. In the presence of hyperparathyroid bone disease, lanthanum was also distributed throughout the mineralized trabecular bone. No correlation with the presence of osteoid, or the underlying bone pathology could be demonstrated. After a 2- or 4-week washout period before sacrifice, lanthanum localization did not change significantly. CONCLUSION: The comparable localization of lanthanum in different types of bone turnover, and the unchanged localization after washout and consequent disappearance of the mineralization defect, indicates no relationship between the localization of lanthanum in bone and the presence of a mineralization defect.
Administration, Oral↗
Hyaluronan is apically secreted and expressed by proliferating or regenerating renal tubular cells.
BACKGROUND: Hyaluronan has diverse biologic functions in the body, varying from structural tasks to cell stress-induced CD44-mediated activation of intracellular signaling pathways. Hyaluronan biology is relatively unexplored in the kidney. Previously, we identified hyaluronan as binding molecule for crystals in the renal tubules. Crystal retention is a crucial early event in the etiology of kidney stones. The present study was performed to determine the polarized distribution of hyaluronan and CD44 by renal tubular cells. METHODS: Madin-Darby canine kidney (MDCK) strain I and primary cultures of human renal tubular cells were grown on permeable supports in a two-compartment culture system. Studies were performed during growth and after scrape-injury. Metabolic labeling studies and an enzyme-linked hyaluronan -binding assay were used to measure the molecular mass and the amount of secreted hyaluronan in apical and basal medium. Confocal microscopy was applied to detect membrane hyaluronan and CD44. Hyaluronan synthase (HAS) mRNA expression was studied with reverse transcriptase-polymerase chain reaction (RT-PCR). The in vitro expression profile of hyaluronan was compared with that in biopsies of transplanted human kidneys with acute tubular necrosis. RESULTS: Proliferating cells produced more hyaluronan (M(r) > 10(6) Da) than growth-inhibited cells in intact monolayers and up to 85% was targeted to the apical compartment, which was accompanied by increased HAS2 mRNA expression and slightly decreased HAS3 mRNA, while HAS1 mRNA remained undetectable. Hyaluronan and CD44 were exclusively expressed at the apical surface of proliferating/regenerating cells. After (re)establishment of tight junctions, hyaluronan was no longer detectable while CD44 was targeted to basolateral membrane domains. In vivo in inflamed human kidneys hyaluronan was abundantly expressed in the cortical tubulointerstitial space as well as at the luminal surface of regenerating renal tubular cells. CONCLUSION: These results demonstrate that the production of hyaluronan by renal tubular cells is activated during proliferation and in response to mechanical injury and that hyaluronan and CD44 expression is highly polarized. The targeted delivery of hyaluronan to the apical compartment suggests that hyaluronan produced by renal tubular cells supports proliferation/regeneration in the renal tubules, but that it does not contribute to hyaluronan accumulation in the renal interstitium. These data further support the concept that mitogen/stress-induced hyaluronan deposition in the renal tubules increases the risk for crystal retention and stone formation.
Animals↗
Lanthanum pharmacokinetics: are rat data misleading?
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Animals↗
Preconditioning of the distal tubular epithelium of the human kidney precedes nephrocalcinosis.
BACKGROUND: Preterm neonates and renal transplant patients frequently develop nephrocalcinosis. Experimental studies revealed that crystal retention in the distal nephron, a process that may lead to nephrocalcinosis, is limited to proliferating/regenerating tubular cells expressing hyaluronan and osteopontin at their luminal surface. Fetal and transplant kidneys contain proliferating and/or regenerating cells since nephrogenesis is not completed until 36 weeks of gestation, while ischemia and nephrotoxic immunosuppressants may lead to injury and repair in renal transplants. This prompted us to investigate the expression of hyaluronan and osteopontin and to correlate this to the appearance of tubular calcifications both in fetal/preterm and transplanted kidneys. METHODS: Sections of fetal/preterm kidneys and protocol biopsies of transplanted kidneys (12 and 24 weeks posttransplantation from the same patients) were stained for osteopontin, hyaluronan, and calcifications (von Kossa). RESULTS: Hyaluronan and osteopontin were expressed at the luminal surface of the epithelial cells lining the distal tubules of all fetal kidneys at birth and in all kidney graft protocol biopsies 12 and 24 weeks posttransplantation. In 7 out of 18 surviving (at least 4 days) preterm neonates crystal retention developed. In renal allografts a striking increase (from 2/10 to 6/10) in tubular crystal retention between 12 and 24 weeks posttransplantation was observed. In addition, crystals were selectively retained in distal renal tubules containing cells with hyaluronan and osteopontin at their luminal surface. CONCLUSION: The results of this study show that luminal expression of hyaluronan and osteopontin preceded renal distal tubular retention of crystals in preterm neonates and renal transplant patients. We propose that the presence of this crystal binding phenotype may play a general role in renal calcification processes.
Cell Division↗
Effects of efficient phosphate binding on bone in chronic renal failure rats.
BACKGROUND: We recently reported that administration of high doses of lanthanum carbonate (1000 mg/kg/day) to chronic renal failure (CRF) rats can result in a mineralization defect. Our results suggested, however, that the impaired mineralization was not due to a direct toxic action of lanthanum on the bone, but rather was an indirect consequence of a phosphate depletion resulting from the compound's high phosphate-binding capacity. To further substantiate these results, in the present study, the effects of lanthanum carbonate on bone were compared to the effects of sevelamer, a nonabsorbed, non-metal-containing polymeric phosphate-binding agent. METHODS: Male Wistar rats underwent a 5/6th nephrectomy to induce chronic renal failure, after which they were treated with either sevelamer (500 or 1000 mg/kg/day) or lanthanum carbonate (1000 mg/kg/day) by oral gavage for 12 weeks. RESULTS: CRF animals treated with either sevelamer (500 or 1000 mg/kg/day) or lanthanum carbonate (1000 mg/kg/day) developed a phosphate depletion after 4 weeks of treatment, as evidenced by a marked reduction in phosphaturia. At sacrifice after 12 weeks of treatment, bone histomorphometry showed that a mineralization defect had developed in two out of six animals in the lanthanum-carbonate-treated group, in four out of seven animals in the 1000 mg/kg/ day sevelamer group, and in one out of nine animals in the 500 mg/kg/day sevelamer group. CONCLUSIONS: These results corroborate our previous findings that the administration of a powerful phosphate-binding agent to CRF rats can induce phosphate depletion, resulting in a mineralization defect.
Animals↗
Cellular infiltrates and injury evaluation in a rat model of warm pulmonary ischemia-reperfusion.
INTRODUCTION: Beside lung transplantation, cardiopulmonary bypass, isolated lung perfusion and sleeve resection result in serious pulmonary ischemia-reperfusion injury, clinically known as acute respiratory distress syndrome. Very little is known about cells infiltrating the lung during ischemia-reperfusion. Therefore, a model of warm ischemia-reperfusion injury was applied to differentiate cellular infiltrates and to quantify tissue damage. METHODS: Fifty rats were randomized into eight groups. Five groups underwent warm ischemia for 60 min followed by 30 min and 1-4 hours of warm reperfusion. An additional group was flushed with the use of isolated lung perfusion after 4 hours of reperfusion. One of two sham groups was also flushed. Neutrophils and oedema were investigated by using samples processed with hematoxylin/eosin stain at a magnification of x500. Immunohistochemistry with antibody ED-1 (magnification x250) and antibody 1F4 (magnification x400) was applied to visualize macrophages and T cells. TdT-mediated dUTP nick end labelling was used for detecting apoptosis. Statistical significance was accepted at P < 0.05. RESULTS: Neutrophils were increased after 30 min until 4 hours of reperfusion as well as after flushing. A doubling in number of macrophages and a fourfold increase in T cells were observed after 30 min until 1 and 2 hours of reperfusion, respectively. Apoptosis with significant oedema in the absence of necrosis was seen after 30 min to 4 hours of reperfusion. CONCLUSIONS: After warm ischemia-reperfusion a significant increase in infiltration of neutrophils, T cells and macrophages was observed. This study showed apoptosis with serious oedema in the absence of necrosis after all periods of reperfusion.
Animals↗
Postmenopausal osteoporosis and strontium ranelate.
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Bone Density↗
Improving outcomes in hyperphosphataemia.
Preclinical studies have shown that lanthanum has a very high phosphate-binding capacity at gastrointestinal pH, while clinical trials have shown lanthanum carbonate to be an effective, well-tolerated phosphate binder for the treatment of hyperphosphataemia in patients with end-stage renal disease. Optimization of bone health is an important issue in these patients, and, based on theoretical grounds, there have been concerns that lanthanum will have toxic effects on bone similar to those of aluminium. However, compared with aluminium, absorption of lanthanum is extremely low and lanthanum treatment is not associated with systemic toxicity. In addition, unlike aluminium, elimination of lanthanum is not through the kidney, but mainly takes place via the biliary route and is, therefore, independent of renal function. This implies that patients with chronic renal failure are not at an increased risk for accumulation of the element, compared with patients with normal renal function. In animal studies, no adverse effects on bone were seen in healthy animals receiving lanthanum carbonate. In 5/6th nephrectomized rats, very high doses of lanthanum (1000-2000 mg/kg) affected bone mineralization. This was not due to a direct toxic effect on bone, but was secondary to phosphate depletion induced by lanthanum and, as with any gastro-intestinal phosphate-binding agent, can be reversed with a phosphate-supplemented diet. In a phase III clinical trial, bone biopsies were taken from dialysis patients at baseline and after 1 year of treatment with either lanthanum carbonate (median dose, 1250 mg/day) or calcium carbonate (median dose, 2000 mg/day). Patients treated with lanthanum carbonate for 1 year did not experience any of the aluminium-like toxic effects on bone expressed as either osteomalacia or adynamic bone disease.
Clinical Trials, Phase II as Topic↗
Does the phosphate binder lanthanum carbonate affect bone in rats with chronic renal failure?
Adequate control of phosphate levels remains an important issue in patients with chronic renal failure (CRF). Lanthanum carbonate has been proposed as a new phosphate binder. Previous studies have shown a high phosphate binding capacity (>97%) and low gastrointestinal absorption of lanthanum, without serious toxic side effects in the presence of a normal renal function (NRF). Because of lanthanum's physicochemical resemblance to calcium, the possible effects of it on bone have to be considered. The aim of this study was to investigate the effects of lanthanum carbonate on bone histology in NRF and CRF rats after oral administration of the compound with doses of 100, 500, or 1000 mg/kg per d for 12 wk. Bone histomorphometry showed that CRF animals that received vehicle developed secondary hyperparathyroidism. Urinalysis of lanthanum-loaded CRF animals showed a dose-dependent decrease in urinary phosphorus excretion, which was clearly more pronounced in the CRF groups compared with NRF animals. Phosphatemia, however, remained normal. Lanthanum carbonate administration induced a dose-dependent decrease in bone formation rate and increase in osteoid area in CRF animals. Three of seven animals in the CRF-1000 group and one of eight animals in the NRF-100 group were classified as having a mineralization defect. The number of cuboidal osteoblasts, however, was not affected, indicating that bone changes were not due to a toxic effect of lanthanum on the osteoblast. Furthermore, lanthanum concentrations in the femur remained low and did not correlate with histomorphometric parameters. These findings suggest that the administration of high doses of phosphate binder (1000 mg/kg per d lanthanum carbonate), in combination with decreased 25-(OH) vitamin D(3) in the uremic state, resulted in phosphate depletion and followed by an increased mobilization of phosphorus out of bone and/or reduced incorporation into bone. There was no evidence that lanthanum had a direct toxic effect on osteoblasts.
Alkaline Phosphatase↗
Inhibitors of HMG-CoA reductase reduce receptor-mediated endocytosis in human kidney proximal tubular cells.
The proximal tubular cells of the kidney are responsible for reabsorption of proteins from the tubular lumen. In a study using Opossum kidney (OK) cells, receptor-mediated protein endocytosis was reduced by statins, inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, which are widely used for therapeutic reduction of plasma cholesterol levels. To explore the possible clinical relevance of the observations in OK cells, protein endocytosis in human kidney tubular cells was investigated in the presence and absence of statins. The uptake of FITC-labeled albumin in these cultures of human kidney tubular cells was investigated by microscopy, flow cytometry and spectrofluorometry. Protein uptake occurred selectively into proximal tubular cells while it was absent in distal tubular/collecting duct cells. Three statins (simvastatin, pravastatin, and rosuvastatin) significantly inhibited the uptake of protein in a concentration-dependent way. This inhibitory effect of statins could be prevented by the co-addition of mevalonate, the product of HMG-CoA reductase. This effect was not the result of a statin-induced cytotoxicity since cell-viability was unaffected. Finally, it was demonstrated that statins strongly inhibited cholesterol synthesis in the human kidney tubular cells. These data suggest that statins have the potential to inhibit albumin uptake by the human proximal nephron as a result of inhibition of HMG-CoA reductase in the proximal tubule cells. Taken into account the data of the accompanying manuscript this inhibitory effect most probably results from a reduced prenylation of some proteins critically involved in endocytosis. It is suggested that these data help to explain the occurrence of proteinuria in some patients treated with high statin doses.
Cells, Cultured↗
Lanthanum carbonate: a new phosphate binder.
PURPOSE OF REVIEW: Hyperphosphatemia remains an important aspect in the management of end-stage renal disease patients. Consequently, there is a need for new, efficient and well-tolerated phosphate binders. In this review, a new phosphate-binding drug, lanthanum carbonate, with an attractive preclinical efficacy profile compared with existing binders, is discussed. Although the available human efficacy and safety data over 3 years are encouraging, the consequences of low-level tissue deposition continue to be evaluated in longer-term clinical studies. RECENT FINDINGS: Lanthanum carbonate has been shown in clinical studies of up to 3 years to be an effective, well-tolerated phosphate binder. Reported adverse effects are mainly gastrointestinal, and do not differ from those of calcium carbonate. The gastrointestinal absorption of lanthanum is very low. Whereas the element is mainly excreted by the liver, renal excretion of the absorbed fraction is less than 2%. Bone lanthanum levels seen after long-term treatment (up to 4 years) seem not to affect the physicochemical process of mineralization, or osteoblast number/function. Preliminary data on the localization of lanthanum in bone have shown the element to be present at both active and quiescent sites of bone mineralization, independent of the type of renal osteodystrophy, a profile distinct from aluminum, as well as diffusely distributed throughout the mineralized bone matrix especially in rats/humans with an increased bone turnover. A randomized, comparator-controlled, parallel group, open-label study comparing lanthanum carbonate with calcium carbonate in dialysis patients showed no evolution towards low bone turnover in the lanthanum group, and no aluminum-like effect on bone. SUMMARY: Lanthanum carbonate seems to be a potent phosphate-binding drug, minimally absorbed from the gut, with an encouraging safety profile, and no deleterious effects on bone.
Bone and Bones↗
T cells as mediators in renal ischemia/reperfusion injury.
Inflammation has been established to contribute substantially to the pathogenesis of ischemia/reperfusion (I/R) with a central role for particular cells, adhesion molecules, and cytokines. Until recently, most of the research trying to unravel the pathogenesis of I/R injury has been focused on the role of neutrophils. However, recent studies have brought evidence that T cells and macrophages are also important leukocyte mediators of renal and extrarenal (liver) I/R injury. In vivo depletion of CD4+ cells but not CD8+ cells in wild-type mice was protective in I/R of the kidney. A marked preservation of liver function was also found after I/R in T-cell deficient athymic mice. Blocking the b130/CD28 costimulatory pathway by CTLA-4 Ig (recombinant fusion protein) ameliorated renal dysfunction and decreased mononuclear cell infiltration in I/R of the kidney. b130-1 expression was found limited to the membrane of the endothelial cells of the ascending vasa recta, resulting in trapping of CD28-expressing CD4 T cells. This trapping of leukocytes results in the upstream congestion in the ascending arterial vasa recta, generating the since more than 150 years described medullary vascular congestion of the kidney soon after ischemic injury. It seems worthwhile to study a combination therapy using anti-inflammatory/anti-adhesion molecules in the early phase of I/R.
Acute Kidney Injury↗