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JAMA May 2021Among patients with hyperphosphatemia undergoing dialysis, it is unclear whether non-calcium-based phosphate binders are more effective than calcium-based binders for... (Comparative Study)
Comparative Study Randomized Controlled Trial
Effect of Treating Hyperphosphatemia With Lanthanum Carbonate vs Calcium Carbonate on Cardiovascular Events in Patients With Chronic Kidney Disease Undergoing Hemodialysis: The LANDMARK Randomized Clinical Trial.
IMPORTANCE
Among patients with hyperphosphatemia undergoing dialysis, it is unclear whether non-calcium-based phosphate binders are more effective than calcium-based binders for reducing cardiovascular events.
OBJECTIVE
To determine whether lanthanum carbonate reduces cardiovascular events compared with calcium carbonate in patients with hyperphosphatemia at risk of vascular calcification undergoing hemodialysis.
DESIGN, SETTING, AND PARTICIPANTS
Open-label, randomized, parallel-group clinical trial with blinded end point adjudication performed in 2374 patients with chronic kidney disease from 273 hemodialysis facilities in Japan. Eligible patients had hyperphosphatemia and 1 or more risk factors for vascular calcification (ie, ≥65 years, postmenopausal, diabetes). Enrollment occurred from November 2011 to July 2014; follow-up ended June 2018.
INTERVENTIONS
Patients were randomized to receive either lanthanum carbonate (n = 1154) or calcium carbonate (n = 1155) and titrated to achieve serum phosphate levels of between 3.5 mg/dL and 6.0 mg/dL.
MAIN OUTCOMES AND MEASURES
The primary outcome was a composite cardiovascular event (cardiovascular death, nonfatal myocardial infarction or stroke, unstable angina, transient ischemic attack, or hospitalization for heart failure or ventricular arrhythmia). Secondary outcomes included overall survival, secondary hyperparathyroidism-free survival, hip fracture-free survival, and adverse events.
RESULTS
Among 2309 randomized patients (median age, 69 years; 40.5% women), 1851 (80.2%) completed the trial. After a median follow-up of 3.16 years, cardiovascular events occurred in 147 of 1063 patients in the lanthanum calcium group and 134 of 1072 patients in the calcium carbonate group (incidence rate, 4.80 vs 4.30 per 100 person-years; difference 0.50 per 100 person-years [95% CI, -0.57 to 1.56]; hazard ratio [HR], 1.11 [95%, CI, 0.88 to 1.41], P = .37). There were no significant differences in all-cause death (difference, 0.43 per 100 person-years [95% CI, -0.63 to 1.49]; HR, 1.10 [95% CI, 0.88 to 1.37]; P = .42) or hip fracture (difference, 0.10 per 100 person-years [95% CI, -0.26 to 0.47]; HR, 1.21 [95% CI, 0.62 to 2.35]; P = .58). The lanthanum carbonate group had an increased risk of cardiovascular death (difference, 0.61 per 100 person-years [95% CI, 0.02 to 1.21]; HR, 1.51 [95% CI, 1.01 to 2.27]; P = .045) and secondary hyperparathyroidism (difference, 1.34 [95% CI, 0.49 to 2.19]; HR, 1.62 [95% CI, 1.19 to 2.20]; P = .002). Adverse events occurred in 282 (25.7%) in the lanthanum carbonate group and 259 (23.4%) in the calcium carbonate groups.
CONCLUSIONS AND RELEVANCE
Among patients undergoing hemodialysis with hyperphosphatemia and at least 1 vascular calcification risk factor, treatment of hyperphosphatemia with lanthanum carbonate compared with calcium carbonate did not result in a significant difference in composite cardiovascular events. However, the event rate was low, and the findings may not apply to patients at higher risk.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01578200; UMIN Clinical Trial Registry Identifier: UMIN000006815.
Topics: Aged; Calcium Carbonate; Cardiovascular Diseases; Female; Heart Disease Risk Factors; Hip Fractures; Humans; Hyperparathyroidism; Hyperphosphatemia; Incidence; Japan; Lanthanum; Male; Phosphates; Renal Dialysis; Renal Insufficiency, Chronic; Survival Analysis; Vascular Calcification
PubMed: 34003226
DOI: 10.1001/jama.2021.4807 -
Journal of the American Society of... Mar 2021In patients on maintenance dialysis, cardiovascular mortality risk is remarkably high, which can be partly explained by severe coronary artery calcification (CAC).... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In patients on maintenance dialysis, cardiovascular mortality risk is remarkably high, which can be partly explained by severe coronary artery calcification (CAC). Hyperphosphatemia has been reported to be associated with the severity of CAC. However, the optimal phosphate range in patients on dialysis remains unknown. This study was planned to compare the effects on CAC progression of two types of noncalcium-based phosphate binders and of two different phosphate target ranges.
METHODS
We conducted a randomized, open-label, multicenter, interventional trial with a two by two factorial design. A total of 160 adults on dialysis were enrolled and randomized to the sucroferric oxyhydroxide or lanthanum carbonate group, with the aim of reducing serum phosphate to two target levels (3.5-4.5 mg/dl in the strict group and 5.0-6.0 mg/dl in the standard group). The primary end point was percentage change in CAC scores during the 12-month treatment.
RESULTS
The full analysis set included 115 patients. We observed no significant difference in percentage change in CAC scores between the lanthanum carbonate group and the sucroferric oxyhydroxide group. On the other hand, percentage change in CAC scores in the strict group (median of 8.52; interquartile range, -1.0-23.9) was significantly lower than that in the standard group (median of 21.8; interquartile range, 10.0-36.1; =0.006). This effect was pronounced in older (aged 65-74 years) versus younger (aged 20-64 years) participants ( value for interaction =0.003). We observed a similar finding for the absolute change in CAC scores.
CONCLUSIONS
Further study with a larger sample size is needed, but strict phosphate control shows promise for delaying progression of CAC in patients undergoing maintenance hemodialysis.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
Evaluate the New Phosphate Iron-Based Binder Sucroferric Oxyhydroxide in Dialysis Patients with the Goal of Advancing the Practice of EBM (EPISODE), jRCTs051180048.
Topics: Adult; Aged; Calcinosis; Coronary Artery Disease; Disease Progression; Drug Combinations; Female; Ferric Compounds; Humans; Hyperphosphatemia; Lanthanum; Male; Middle Aged; Phosphates; Renal Dialysis; Sequestering Agents; Sucrose; Young Adult
PubMed: 33547218
DOI: 10.1681/ASN.2020050598 -
Journal of Trace Elements in Medicine... May 2022Studies dealing with Rare Earth Elements (REE) ecotoxicological behavior are scattered and with potential conflicting results. Climate change impacts on aquatic biota...
Studies dealing with Rare Earth Elements (REE) ecotoxicological behavior are scattered and with potential conflicting results. Climate change impacts on aquatic biota and is known to modify contaminants toxicokinetic. Nevertheless, the current knowledge on the potential interactions between climate change and REE is virtually non-existent. Therefore, we focus our research on La and Gd as representatives of Light and Heavy REE that also are of great environmental concern. Experiments on different mediums (fresh-, brackish- and seawater) were designed to run at present-day and near-future conditions (T°=+4 °C, pH=△-0.4). Sampling was taken at different time scales from minutes to hours for one day. The main challenge was to evaluate the availability of La and Gd under environmental conditions closely related to climate changes scenarios. Furthermore, this study will contribute to the baseline knowledge by which future research towards understanding REE patterns and toxicity will build upon. Lanthanum and Gd behave differently with salinity. Temperature also affects the availability of dissolved La in freshwater. On the other hand, pH reduction causes the decrease of Gd in freshwater. In this medium, concentrations reduce sharply, presumably due to sorption processes or precipitates. In the brackish water experiment only the dissolved La levels in the Warming (T°=+4 °C) and Warming & Acidification (T°=+4 °C, pH=△0.4) diminished significantly through time. Dissolved La and Gd levels in seawater were relatively constant with time. The speciation of both elements is also of great relevance for ecotoxicological experiments. The trivalent free ions (La and Gd) were the most common species in the trials. However, as ionic strength increases, the availability of other complexes rose, which should be subject of great attention for upcoming ecotoxicological studies.
Topics: Gadolinium; Lanthanum; Ecotoxicology; Water Pollutants, Chemical; Environmental Monitoring; Metals, Rare Earth
PubMed: 35227975
DOI: 10.1016/j.jtemb.2022.126957 -
Nephrology (Carlton, Vic.) Dec 2016Despite 10 years of post-marketing safety monitoring of the phosphate binder lanthanum carbonate, concerns about aluminium-like accumulation and toxicity persist.... (Review)
Review
Despite 10 years of post-marketing safety monitoring of the phosphate binder lanthanum carbonate, concerns about aluminium-like accumulation and toxicity persist. Here, we present a concise overview of the safety profile of lanthanum carbonate and interim results from a 5-year observational database study (SPD405-404; ClinicalTrials.gov identifier: NCT00567723). The pharmacokinetic paradigms of lanthanum and aluminium are different in that lanthanum is minimally absorbed and eliminated via the hepatobiliary pathway, whereas aluminium shows appreciable absorption and is eliminated by the kidneys. Randomised prospective studies of paired bone biopsies revealed no evidence of accumulation or toxicity in patients treated with lanthanum carbonate. Patients treated with lanthanum carbonate for up to 6 years showed no clinically relevant changes in liver enzyme or bilirubin levels. Lanthanum does not cross the intact blood-brain barrier. The most common adverse effects are mild/moderate nausea, diarrhoea and flatulence. An interim Kaplan-Meier analysis of SPD405-404 data from the United States Renal Data System revealed that the median 5-year survival was 51.6 months (95% CI: 49.1, 54.2) in patients who received lanthanum carbonate (test group), 48.9 months (95% CI: 47.3, 50.5) in patients treated with other phosphate binders (concomitant therapy control group) and 40.3 months (95% CI: 38.9, 41.5) in patients before the availability of lanthanum carbonate (historical control group). Bone fracture rates were 5.9%, 6.7% and 6.4%, respectively. After more than 850 000 person-years of worldwide patient exposure, there is no evidence that lanthanum carbonate is associated with adverse safety outcomes in patients with end-stage renal disease.
Topics: Adult; Aged; Animals; Biomarkers; Chelating Agents; Clinical Trials, Phase IV as Topic; Databases, Factual; Female; Humans; Hyperphosphatemia; Kaplan-Meier Estimate; Kidney Failure, Chronic; Lanthanum; Male; Middle Aged; Patient Safety; Phosphates; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome
PubMed: 27479781
DOI: 10.1111/nep.12864 -
Renal Failure Dec 2021The aim of this study was to determine the efficacy and safety of lanthanum carbonate (LC) versus calcium salts, non-LC phosphate binders (PBs), sevelamer, or placebo in... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The aim of this study was to determine the efficacy and safety of lanthanum carbonate (LC) versus calcium salts, non-LC phosphate binders (PBs), sevelamer, or placebo in patients with chronic kidney disease (CKD).
MATERIALS AND METHODS
A literature search on PubMed, Embase, and Cochrane Library databases was conducted up to 18 June 2021. Data acquisition and quality assessment were performed by two reviewers. Meta-analysis was performed to evaluate the serum biochemical parameters, adverse events, and patient-level outcomes of LC, non-LC PBs, and sevelamer for hyperphosphatemia in patients with CKD. Heterogeneity across studies was assessed utilizing the statistic and -test, and a random effect model was selected to calculate the pooled effect size.
RESULTS
A total of 26 randomized, controlled trials and 3 observational studies were included. Compared to the other groups, better control effect of serum phosphorus (RR = 2.68, < 0.001), reduction in serum phosphorus (95%CI = -1.93, -0.99; < 0.001), Ca × P (95%CI = -13.89, -2.99; = 0.002), serum intact parathyroid hormone levels (95%CI = -181.17, -3.96, = 0.041) were found in LC group. Besides, reduced risk of various adverse effects, such as hypotension, abdominal pain, diarrhea, dyspepsia, and a score of coronary artery calcification were identified with LC in comparison to calcium salt, non-LC PBs, or placebo group. Significantly lower risk in mortality with LC treatment vs. non-LC PBs was observed, while no significant difference was identified between LC and calcium salt groups.
CONCLUSION
LC might be an alternative treatment for hyperphosphatemia in patients with CKD considering its comprehensive curative effect.
Topics: Chronic Kidney Disease-Mineral and Bone Disorder; Humans; Hyperphosphatemia; Lanthanum; Observational Studies as Topic; Parathyroid Hormone; Phosphates; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Sevelamer; Treatment Outcome
PubMed: 34602015
DOI: 10.1080/0886022X.2021.1986068 -
World Journal of Gastroenterology Apr 2020Lanthanum carbonate is used for treatment of hyperphosphatemia mostly in patients with chronic renal failure. Although lanthanum carbonate is safe, recently, lanthanum... (Review)
Review
Lanthanum carbonate is used for treatment of hyperphosphatemia mostly in patients with chronic renal failure. Although lanthanum carbonate is safe, recently, lanthanum deposition in the gastrointestinal mucosa of patients has been reported in the literature. This review provides an overview of gastroduodenal lanthanum deposition and focuses on disease's endoscopic, radiological, and histological features, prevalence, and outcome, by reviewing relevant clinical studies, case reports, and basic research findings, to better understand the endoscopic manifestation of gastrointestinal lanthanum deposition. The possible relationship between gastric lanthanum deposition pattern and gastric mucosal atrophy is also illustrated; in patients without gastric mucosal atrophy, gastric lanthanum deposition appears as diffuse white lesions in the posterior wall and lesser curvature of the gastric body. In the gastric mucosa with atrophy, lanthanum-related lesions likely appear as annular or granular whitish lesions. Moreover, these white lesions are probably more frequently observed in the lower part of the stomach, where intestinal metaplasia begins.
Topics: Atrophy; Gastric Mucosa; Gastrointestinal Diseases; Gastrointestinal Tract; Humans; Hyperphosphatemia; Kidney Failure, Chronic; Lanthanum
PubMed: 32308345
DOI: 10.3748/wjg.v26.i13.1439 -
Kidney International May 2009Hyperphosphatemia is an inevitable consequence of end-stage chronic kidney disease and is present in the majority of dialysis patients. Hyperphosphatemia is... (Review)
Review
Hyperphosphatemia is an inevitable consequence of end-stage chronic kidney disease and is present in the majority of dialysis patients. Hyperphosphatemia is observationally and statistically associated with increased cardiovascular mortality among dialysis patients. Dietary restriction of phosphate and current dialysis modalities are not sufficiently effective to maintain serum phosphate levels within the recommended range, so the majority of dialysis patients require oral phosphate binders. However, the benefits of achieving the recommended range have yet to be shown prospectively. Unfortunately, conventional phosphate binders are not reliably effective and are associated with a range of limitations and side effects. Aluminum-containing agents are highly efficient but no longer widely used because of proven toxicity. Calcium-based salts are inexpensive, effective, and most widely used, but there is now concern about their association with hypercalcemia and vascular calcification. Sevelamer hydrochloride is associated with fewer adverse effects, but a large pill burden and high cost are limiting factors to its wider use. Lanthanum carbonate is another non-aluminum, calcium-free phosphate binder. Preclinical and clinical studies have shown a good safety profile, and it appears to be well tolerated and effective in reducing phosphate levels in dialysis patients; however, it is similarly expensive. Data on its safety profile over 6 years of treatment are now published. Achievement of opinion-based guidelines appears to have become an end in itself. Dialysis patient outcomes are worse than outcomes for many types of cancer, yet prospective, outcome-based randomized controlled trials are not being undertaken for reasons that are difficult to explain.
Topics: Chelating Agents; Humans; Hyperphosphatemia; Lanthanum; Phosphates; Polyamines; Renal Dialysis; Sevelamer
PubMed: 19279554
DOI: 10.1038/ki.2009.60 -
Kidney International Feb 2009Mineral metabolism in chronic kidney disease is attracting intense interest and unprecedented levels of research. The pharmaceutical industry has responded by developing... (Review)
Review
Mineral metabolism in chronic kidney disease is attracting intense interest and unprecedented levels of research. The pharmaceutical industry has responded by developing various new agents. Bervoets et al. report the use of an unusual combination of basic-science techniques to increase understanding of the kinetics of one such agent--lanthanum carbonate--in the gastrointestinal tract and liver. However, do we need to answer more fundamental clinical questions before we can definitively identify the role of similar new and expensive drugs?
Topics: Gastrointestinal Tract; Humans; Kidney Failure, Chronic; Lanthanum; Liver; Middle Aged; Minerals; Phosphates
PubMed: 19180150
DOI: 10.1038/ki.2008.627 -
Environmental Science and Pollution... Nov 2022Graphite (GR) and graphite/alginate (GRA) composite were synthesized utilizing the thermal annealing technique and used as a new adsorbent material for the selective...
Graphite (GR) and graphite/alginate (GRA) composite were synthesized utilizing the thermal annealing technique and used as a new adsorbent material for the selective separation and removal of La(III) and Ce(III) from aqueous solutions. Fourier transform infrared (FTIR) spectroscopy, thermal analysis (DTA, TGA), X-ray diffraction (XRD), surface area, porosity, and scanning electron microscope (SEM) were also used to characterize the generated material. Distinct experiments were performed to test the ability of the GRA to La(III) and Ce(III) removal, which include the effect of pH, shaken time, initial concentration of La(III), and Ce(III) at different temperatures range. After 20 min, both ions have reached equilibrium. The pseudo second-order kinetic model was chosen as one which best fits the experimental evidence and better reflects the chemical sorption process. Adsorption isotherm was studied using the Langmuir, Freundlich, and D-R models. The Langmuir model was used to better fit the results obtained. At 25 °C, Ce(III) and La(III) have maximum monolayer capacities of 200 and 83.3 mg/g, respectively. The sorption was endothermic reaction and spontaneous, as illustrated by the data of thermodynamics studies. GRA has the ability to be used as a novel lanthanide adsorbent material, especially for selective separation between Ce(III) and La(III).
Topics: Graphite; Lanthanum; Cerium; Feasibility Studies; Adsorption; Kinetics; Thermodynamics; Spectroscopy, Fourier Transform Infrared; Alginates; Ions; Hydrogen-Ion Concentration; Water Pollutants, Chemical
PubMed: 35713835
DOI: 10.1007/s11356-022-20823-9 -
Chemosphere Jan 2020Among several other eutrophication management tools, Phoslock®, a lanthanum modified bentonite (LMB) clay, is now frequently used. Concerns have been raised as to...
Among several other eutrophication management tools, Phoslock®, a lanthanum modified bentonite (LMB) clay, is now frequently used. Concerns have been raised as to whether exposure to Phoslock®-treated water may lead to lanthanum accumulation/toxicity in both animals and humans. In the present experimental study, rats were administered lanthanum orally as either lanthanum carbonate, lanthanum chloride or Phoslock® at doses of either 0.5 or 17 mg/L during 10 weeks. Controls received vehicle. The gastrointestinal absorption and tissue distribution of lanthanum was investigated. Extremely strict measures were implemented to avoid cross-contamination between different tissues or animals. Results showed no differences in gastrointestinal absorption between the different compounds under study as reflected by the serum lanthanum levels and concentrations found in the brain, bone, heart, spleen, lung, kidney and testes. At sacrifice, significant but equally increased lanthanum concentrations versus vehicle were observed in the liver for the highest dose of each compound which however, remained several orders of magnitude below the liver lanthanum concentration previously measured after long-term therapeutic administration of lanthanum carbonate and for which no hepatotoxicity was noticed in humans. In conclusion, (i) the use of LMB does not pose a toxicity risk (ii) gastrointestinal absorption of lanthanum is minimal and independent on the type of the compound, (iii) with exception of the liver, no significant increase in lanthanum levels is observed in the various organs under study, (iv) based on previous studies, the slightly increased liver lanthanum levels observed in a worst case scenario do not hold any risk of hepatotoxicity.
Topics: Animals; Bentonite; Eutrophication; Lanthanum; Liver; Phosphorus; Rats; Water Purification
PubMed: 31726528
DOI: 10.1016/j.chemosphere.2019.124780