Assessment of osteopontin as an early nephrotoxicity indicator in human renal proximal tubule cells and its application in evaluating lanthanum-induced nephrotoxicity.

Nephrotoxicity is a common adverse effect induced by various chemicals, necessitating the development of reliable toxicity screening models for nephrotoxicity assessment. In this study, we assessed a group of nephrotoxicity indicators derived from different toxicity pathways, including conventional endpoints and kidney tubular injury biomarkers such as clusterin (CLU), kidney injury molecule-I (KIM-1), osteopontin (OPN), and neutrophil gelatinase-associated lipocalin (NGAL), using HK-2 and induced pluripotent stem cells (iPSCs)-derived renal proximal tubular epithelial-like cells (PTLs). Among the biomarkers tested, OPN emerged as the most discerning and precise marker. The predictive potential of OPN was tested using a panel of 10 nephrotoxic and 5 non-nephrotoxic compounds. The results demonstrated that combining OPN with the half-maximal inhibitory concentration (IC50) enhanced the diagnostic accuracy in both cellular models. Additionally, PTLs cells showed superior predictive efficacy for nephrotoxicity compared to HK-2 cells in this investigation. The two cellular models were utilized to evaluate the nephrotoxicity of lanthanum. The findings indicated that lanthanum possesses nephrotoxic properties; however, the degree of nephrotoxicity was relatively low, consistent with the outcomes of in vivo experiments.

A Review of Phosphate Binders in Chronic Kidney Disease: Incremental Progress or Just Higher Costs?

As kidney disease progresses, phosphorus retention also increases, and phosphate binders are used to treat hyperphosphatemia. Clinicians prescribe phosphate binders thinking that reducing total body burden of phosphorus may decrease risks of mineral and bone disorder, fractures, cardiovascular disease, progression of kidney disease, and mortality. Recent meta-analyses suggest that sevelamer use results in lower mortality than use of calcium-containing phosphate binders. However, studies included in meta-analyses show significant heterogeneity, and exclusion or inclusion of specific studies alters results. Since no long-term studies have been conducted to determine whether treatment with any phosphate binder is better than placebo on any hard clinical endpoint (including mortality), it is unclear whether possible benefit with sevelamer represents net benefit of sevelamer, net harm with calcium-containing phosphate binders, or both. Although one meta-analysis suggested that calcium acetate may be more efficacious gram for gram than calcium carbonate as a binder, calcium acetate did not reduce hypercalcemia, and gastrointestinal intolerance was higher. Data are insufficient to determine whether calcium acetate provides lower risk of vascular calcification than calcium carbonate. Fears of lanthanum accumulation in the central nervous system or bone with long-term treatment do not appear to be warranted. Newer iron-containing phosphate binders have potential benefits, such as lower pill burden (sucroferric oxyhydroxide) and improved iron parameters (ferric citrate). The biggest challenge to phosphate binder efficacy is non-adherence. This article reviews the current knowledge regarding safety, effectiveness, and adherence with currently marketed phosphate binders and those in development.

Laboratory assessment of uptake and toxicity of lanthanum (La) in the leaves of Hydrocharis dubia (Bl.) Backer.

Increasing amounts of lanthanum (La) is released into aquatic environments. However, little information is available on the influence of La on aquatic plants. In this study, physiological and ultrastructural responses of Hydrocharis dubia (Bl.) Backer leaves to elevated concentrations of La (up to 160 µM) were investigated. The accumulation of La was found to be increased in a concentration-dependent manner. La disturbed the intrinsic balance of nutrient elements (P, Mg, Ca, Fe, K, and Zn). Pigment content decreased with the rise of the La concentrations and the EC(50) value for chlorophyll was 20 µM on day 7. The antioxidants (superoxide dismutase, peroxidase, catalase, reduced ascorbate, and reduced glutathione) exhibited varied response to the La treatments. Malondialdehyde content enhanced gradually at all La concentrations. The enhancement in proline content was found in a concentration-dependent manner. The amounts of three polypeptides with apparent molecular weights of 61.9, 51.5, and 16.7 kDa, respectively, were gradually diminished, as well as one existing polypeptides with apparent molecular weight of 22.3 kDa, elevating in response to increasing La concentrations. Significant damage to the chloroplast, mitochondrion, and nucleus was imposed by La indicated a general disarray in the cellular functions. The negative effects of La on H. dubia unequivocally indicate that La could exert an adverse influence on aquatic ecosystem and should lead to a more careful discharge of such elements into water environment.

Ecotoxicological assessment of lanthanum with Caenorhabditis elegans in liquid medium.

With their widespread applications in industry, agriculture and many other fields, more and more rare earth elements (REEs) are getting into the environment, especially the aquatic systems. Therefore, understanding the aquatic ecotoxicity of REEs has become more and more important. In the present work, Caenorhabditis elegans (C. elegans) was used as a test organism and life-cycle endpoints were chosen along with elemental assay to evaluate the aquatic toxicity of lanthanum (La), a representative of REEs. The results show La³+ had significant adverse effects on the growth and reproduction of worms above a concentration of 10 µmol L⁻¹. The elemental mapping by microbeam synchrotron radiation X-ray fluorescence (µ-SRXRF) illustrated how La treatment disturbed the metals distribution in the whole body of a single tiny nematode at lower levels. Our results suggested that the high-level REEs in some polluted water bodies would lead to an aquatic ecological crisis. The assessment we performed in the present work could be developed as a standardized test design for aquatic toxicological research.

Assessment of survival in a 2-year comparative study of lanthanum carbonate versus standard therapy.

OBJECTIVE: Epidemiological data link elevated levels of serum phosphorus with increased mortality among patients with chronic kidney disease. Recent data also suggest improved survival with the use of dietary phosphate binders in patients on dialysis. However, few studies have comprehensively evaluated the survival benefit associated with different phosphate binders. A post-hoc survival analysis was undertaken of lanthanum carbonate (Fosrenol *) versus standard therapy. RESEARCH DESIGN AND METHODS: Patients on dialysis enrolled in a phase 3, 2-year, comparative safety study were randomized 1:1 to lanthanum carbonate or standard therapy to treat serum phosphorus to a target of < or =5.9 mg/dL (1.90 mmol/L). Patients (N = 1354) were followed up for survival status during, or after completion of or discontinuation from the study. MAIN OUTCOME MEASURES: Survival was measured by time from first dose of study medication to all-cause mortality or last contact. RESULTS: The distribution of follow-up time was similar in the lanthanum carbonate and standard therapy groups (mean 23.7 versus 23.9 months [median 27.0 versus 26.0 months], respectively). Serum phosphorus levels were similar across treatment groups, as patients were treated to target. At follow-up, 19.9% (135/680) of patients treated with lanthanum carbonate had died versus 23.3% (157/674) on standard therapy (log-rank p = 0.18). In the subgroup of patients aged >65 years (n = 336), 27.0% (44/163) of lanthanum-carbonate-treated patients had died compared with 39.3% (68/173) on standard therapy (log-rank p = 0.04). CONCLUSION: In these survival analyses, overall mortality was similar in the lanthanum carbonate and standard therapy groups, but results suggest that there was a survival benefit associated with lanthanum carbonate treatment for patients aged >65 years, who are likely to carry the greatest burden of vascular calcification. These results were similar to those observed in the Dialysis Clinical Outcomes Revisited study, a prospective trial of sevelamer hydrochloride designed to assess survival.

A comparative review of the efficacy and safety of established phosphate binders: calcium, sevelamer, and lanthanum carbonate.

BACKGROUND: Obstacles to successful management of hyperphosphatemia in chronic kidney disease include inadequate control of dietary phosphate and non-compliance with phosphate-binder therapy. Three major classes of phosphate binders include calcium-based binders, sevelamer HCl, and lanthanum carbonate. SCOPE: A literature search was performed using MEDLINE and EMBASE databases to identify clinical trials from January 1966 to May 2007 comparing classes of phosphate binders with regard to efficacy, safety, compliance, or pharmacoeconomics. Search terms included lanthanum AND sevelamer, lanthanum AND calcium, and sevelamer AND calcium. A total of 1372 articles were identified in the search, with 125 review articles and clinical trials of interest identified. FINDINGS: Calcium-based binders are effective, but their potential to contribute to total body calcium overload and vascular calcification is an important long-term clinical concern. Sevelamer HCl is effective in reducing serum phosphate, has no systemic absorption, and does not increase total body calcium load. However, sevelamer HCl binds bile acids, is not an efficient phosphate binder in an acidic environment, and contributes to metabolic acidosis. Lanthanum carbonate is a potent and selective phosphate binder that retains high affinity for phosphate over a wide pH range, does not bind bile acids or contribute to metabolic acidosis, and has the potential to reduce pill burden and increase patient compliance compared with other phosphate binders. CONCLUSIONS: All three classes of phosphate binders are effective at reducing serum phosphate levels. Lanthanum carbonate may result in increased adherence by decreasing the pill burden.

Biosorption of La, Eu and Yb using Sargassum biomass.

Biosorption of the lanthanides: Lanthanum (La(3+)), Europium (Eu(3+)) and Ytterbium (Yb(3+)) from single-component and multi-component batch systems using Sargassum polycystum Ca-loaded biomass was studied. The ion exchange sorption mechanism was confirmed by the release of calcium ions from the biomass that matched the total number of metal and protons removed from the solution. The metal binding increased with pH due to the decrease of proton concentration in the system, as they also compete for the binding sites. The maximum metal uptake capacity for pH 3, 4 and 5 ranged approximately between (0.8-0.9) mmol g(-1) for La (0.8-0.9) mmol g(-1) for Eu, and (0.7-0.9) mmol g(-1) for Yb. Biosorption from multi-component mixtures was examined at pH 4 using equimolar initial concentrations of the metals. The metal affinity sequence established was Eu>La>Yb, and the maximum metal uptake obtained was 0.29, 0.41, 0.28 mmol g(-1) for La, Eu and Yb, respectively.