Effects of lanthanum carbonate and calcium carbonate on cardiovascular calcification in hemodialysis patients: A systematic review and meta-analysis.

OBJECTIVE: This paper was written to systematically review and meta-analyze the evidence on the efficacy of lanthanum carbonate (LC) and calcium carbonate (CC) and the risk of cardiovascular calcification on hemodialysis (HD) patients. MATERIALS AND METHODS: The Cochrane library, PubMed, Web of Science, Chinese journal full-text database (CNKI), WANGFANG DATA, and Sino Med were searched between January 1946 and December 2020. The literature with respect to the randomized controlled clinical trial comparing LC and CC in HD patients was selected. The main outcomes include coronary artery calcification score (CACS), cardiovascular events, and serum phosphorus (mmol/L). The statistical program used for meta-analysis was Stata V14.0. RESULTS: Of 388 original titles screened, data was extracted from 9 studies (625 participants). LC can significantly reduce the progression of coronary artery calcification compared to CC (standardized mean deviation (SMD) = -0.59, 95% CI: -0.94 to -0.25, p < 0.01). The LC group had lower serum phosphorus levels (SMD = -1.35, 95% CI: -2.33 to -0.36, p < 0.01), lower serum calcium levels (SMD = -1.03, 95% CI: -1.83 to -0.23, p = 0.012), and lower fibroblast growth factor 23 (FGF-23) level (SMD = -4.80, 95% CI: -7.96 to -1.64, p = 0.003) than the CC group. The Egger regression test of CACS showed no potential publication bias (p = 0.72). CONCLUSION: Compared with CC, LC can significantly delay the process of coronary artery calcification, and at the same time reduce patients' serum phosphate, serum calcium, and FGF-23. Therefore, we recommend LC as a phosphorus-lowering drug for HD patients.

Meta-Analysis Treatment Hyperphosphatemia Chronic Renal Failure Based on Nano Lanthanum Hydroxide.

In this study, our aim is to investigate the effect of lanthanum carbonate in chronic treatment renal failure complicated with hyperphosphatemia. Using methods with lanthanum carbonate, hyperphosphatemia, placebos, calcium carbonate, end-stage renal disease as keywords, we searched the Chinese Journal Full-text Database, Chinese sci-tech journal database, Wanfang Data knowledge service platform, web of science, PubMed, and other databases for literature quality; meta analysis was carried out after a subsequent evaluation. The meta analysis results showed a significant difference in the control of the blood phosphorus level between weighted mean difference WMD = -0.60, 95% CI: -0.75~-0.45, lanthanum carbonate and placebo; WMD = -0.01, 95% CI: -0.07~-0.05; the lanthanum carbonate and placebo had no significant difference in the control of the blood calcium levels after treatment; WMD = -29.75, 95% CI: -39.22 for the control of blood PIH level after treatment, indicating that the difference between lanthanum carbonate and placebo in the control of the parathyroid hormone (PTH) level was statistically significant. WMD=0.41, 95% CI: -0.48~0.34; the difference between the lanthanum carbonate and calcium carbonate in the control of the blood phosphorus level was statistically significant; WMD = 0.19, 95% CI: -0.25~0.13, lanthanum carbonate and calcium carbonate were statistically significant in blood control calcium level; WMD = 174.66, 95% CI: -150.86~150.46, lanthanum carbonate and calcium carbonate were statistically significant in the control of blood PIH level; the difference was statistically significant. Conclusion: Lanthanum carbonate can significantly reduce blood phosphorus and PIH complicated hyperphosphatemia, and has no significant effect on blood calcium, which is superior to calcium carbonate in effectiveness.

Comparison of the effects of lanthanum carbonate and calcium carbonate on the progression of cardiac valvular calcification after initiation of hemodialysis.

BACKGROUND: Although mineral metabolism disorder influences cardiac valvular calcification (CVC), few previous studies have examined the effects of non-calcium-containing and calcium-containing phosphate binders on CVC in maintenance hemodialysis patients. The aim of the present study was to compare the effects of lanthanum carbonate (LC) with calcium carbonate (CC) on the progression of CVC in patients who initiated maintenance hemodialysis and to investigate clinical factors related to CVC. METHODS: The current study included 50 subjects (mean age 65 years, 72% males) from our previous randomized controlled trial (LC group, N = 24; CC group, N = 26). CVC was evaluated as CVC score (CVCS) using echocardiography at baseline and 18 months after initiation of hemodialysis. We compared CVCS and the changes between the two groups. We also analyzed the associations between CVCS and any other clinical factors including arterial plaque score (PS) and serum phosphorus levels. RESULTS: Baseline characteristics of study participants including CVCS were almost comparable between the two groups. At 18 months, there were no significant differences in mineral metabolic markers or CVCS between the two groups, and CVCS were significantly correlated with PS (r = 0.39, p < 0.01). Furthermore, changes in CVCS were significantly correlated with average phosphorus levels (r = 0.36, p < 0.05), which were significantly higher in high serum phosphorus and high PS group compared to low serum phosphorus and low PS group (p < 0.05). CONCLUSIONS: In the present study, there were no significant differences between LC and CC with regard to progression of CVC. However, serum phosphorus levels and arterial plaque seem to be important for the progression and formation of CVC in hemodialysis patients.

Nutritional status and survival of maintenance hemodialysis patients receiving lanthanum carbonate.

Background: Hyperphosphatemia and poor nutritional status are associated with increased mortality. Lanthanum carbonate is an effective, calcium-free phosphate binder, but little is known about the long-term impact on mineral metabolism, nutritional status and survival. Methods: We extended the follow-up period of a historical cohort of 2292 maintenance hemodialysis patients that was formed in late 2008. We examined 7-year all-cause mortality according to the serum phosphate levels and nutritional indicators in the entire cohort and then compared the mortality rate of the 562 patients who initiated lanthanum with that of the 562 propensity score-matched patients who were not treated with lanthanum. Results: During a mean ± SD follow-up of 4.9 ± 2.3 years, 679 patients died in the entire cohort. Higher serum phosphorus levels and lower nutritional indicators (body mass index, albumin and creatinine) were each independently associated with an increased risk of death. In the propensity score-matched analysis, patients who initiated lanthanum had a 23% lower risk for mortality compared with the matched controls. During the follow-up period, the serum phosphorus levels tended to decrease comparably in both groups, but the lanthanum group maintained a better nutritional status than the control group. The survival benefit associated with lanthanum was unchanged after adjustment for time-varying phosphorus or other mineral metabolism parameters, but was attenuated by adjustments for time-varying indicators of nutritional status. Conclusions: Treatment with lanthanum is associated with improved survival in hemodialysis patients. This effect may be partially mediated by relaxation of dietary phosphate restriction and improved nutritional status.

Lanthanum carbonate, a phosphate binder, inhibits calcification of implanted aortic allografts in a rat model.

OBJECTIVES: Calcification is one of the major postoperative problems after aortic allograft implantation. We hypothesized that phosphate binders, lanthanum carbonate and calcium carbonate inhibit calcification of implanted aortic allografts and verified this hypothesis using a rat model. METHODS: Aortas were harvested from 4-week-old Brown Norway rats and implanted into the subdermal space of 4-week-old Lewis rats. Twenty-seven recipient Lewis rats were divided into Group N, Group L, and Group C (9 rats per group), which were fed a normal diet, a normal diet containing 3% lanthanum carbonate, and a normal diet containing 3% calcium carbonate, respectively. Implanted aortic allografts were explanted 2 weeks later. Calcification of aortic allografts was evaluated using von Kossa staining and calcium content assay. Calcification score was defined in von Kossa staining as 0 (none), 1 (mild), 2 (moderate), and 3 (severe). Serum calcium and phosphorus levels at euthanasia were measured. RESULTS: Calcification scores were 2.6, 1.2, and 0.8, and calcium content was 48.9, 15.8, and 8.9 mg/dry·g, in Groups N, L, and C, respectively. Calcification was significantly reduced in Groups L and C. Serum calcium level was 11.5, 12.2, and 13.5 mg/dl, and serum phosphorus level was 15.4, 12.5, and 11.7 mg/dl, in Groups N, L, and C, respectively. Serum calcium level in Group C was significantly higher than in the other two groups. CONCLUSIONS: Lanthanum carbonate and calcium carbonate significantly reduced calcification of implanted aortic allografts in young rats. Although calcium carbonate induced hypercalcemia, lanthanum carbonate has significant potential to inhibit calcification of implanted aortic allografts.

Relationship between Gut Microbiota and Phosphorus Metabolism in Hemodialysis Patients: A Preliminary Exploration.

BACKGROUND: Hyperphosphatemia is a risk factor associated with mortality in patients on maintenance hemodialysis. Gut absorption of phosphate is the major source. Recent studies indicated that the intestinal flora of uremic patients changed a lot compared with the healthy population, and phosphorus is an essential element of bacterial survival and reproduction. The purpose of this study was to explore the role of intestinal microbiota in phosphorus metabolism. METHODS: A prospective self-control study was performed from October 2015 to January 2016. Microbial DNA was isolated from the stools of 20 healthy controls and 21 maintenance hemodialysis patients. Fourteen out of the 21 patients were treated with lanthanum carbonate for 12 weeks. Thus, stools were also collected before and after the treatment. The bacterial composition was analyzed based on 16S ribosomal RNA pyrosequencing. Bioinformatics tools, including sequence alignment, abundance profiling, and taxonomic diversity, were used in microbiome data analyses. Correlations between genera and the serum phosphorus were detected with Pearson's correlation. For visualization of the internal interactions and further measurement of the microbial community, SparCC was used to calculate the Spearman correlation coefficient with the corresponding P value between each two genera. RESULTS: Thirteen genera closely correlated with serum phosphorus and the correlation coefficient was above 0.4 (P < 0.05). We also found that 58 bacterial operational taxonomic units (OTUs) were significantly different and more decreased OTUs were identified and seven genera (P < 0.05) were obviously reduced after using the phosphate binder. Meanwhile, the microbial richness and diversity presented downward trend in hemodialysis patients compared with healthy controls and more downward trend after phosphorus reduction. The co-occurrence network of genera revealed that the network complexity of hemodialysis patients was significantly higher than that of controls, whereas treatment with lanthanum carbonate reduced the network complexity. CONCLUSIONS: Gut flora related to phosphorus metabolism in hemodialysis patients, and improving intestinal microbiota may regulate the absorption of phosphate in the intestine. The use of phosphate binder lanthanum carbonate leads to a tendency of decreasing microbial diversity and lower network complexity.

Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).

BACKGROUND: Phosphate binders are used to reduce positive phosphate balance and to lower serum phosphate levels for people with chronic kidney disease (CKD) with the aim to prevent progression of chronic kidney disease-mineral and bone disorder (CKD-MBD). This is an update of a review first published in 2011. OBJECTIVES: The aim of this review was to assess the benefits and harms of phosphate binders for people with CKD with particular reference to relevant biochemical end-points, musculoskeletal and cardiovascular morbidity, hospitalisation, and death. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 July 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs of adults with CKD of any GFR category comparing a phosphate binder to another phosphate binder, placebo or usual care to lower serum phosphate. Outcomes included all-cause and cardiovascular death, myocardial infarction, stroke, adverse events, vascular calcification and bone fracture, and surrogates for such outcomes including serum phosphate, parathyroid hormone (PTH), and FGF23. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of Bias' tool and used the GRADE process to assess evidence certainty. We estimated treatment effects using random-effects meta-analysis. Results were expressed as risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI) or mean differences (MD) or standardised MD (SMD) for continuous outcomes. MAIN RESULTS: We included 104 studies involving 13,744 adults. Sixty-nine new studies were added to this 2018 update.Most placebo or usual care controlled studies were among participants with CKD G2 to G5 not requiring dialysis (15/25 studies involving 1467 participants) while most head to head studies involved participants with CKD G5D treated with dialysis (74/81 studies involving 10,364 participants). Overall, seven studies compared sevelamer with placebo or usual care (667 participants), seven compared lanthanum to placebo or usual care (515 participants), three compared iron to placebo or usual care (422 participants), and four compared calcium to placebo or usual care (278 participants). Thirty studies compared sevelamer to calcium (5424 participants), and fourteen studies compared lanthanum to calcium (1690 participants). No study compared iron-based binders to calcium. The remaining studies evaluated comparisons between sevelamer (hydrochloride or carbonate), sevelamer plus calcium, lanthanum, iron (ferric citrate, sucroferric oxyhydroxide, stabilised polynuclear iron(III)-oxyhydroxide), calcium (acetate, ketoglutarate, carbonate), bixalomer, colestilan, magnesium (carbonate), magnesium plus calcium, aluminium hydroxide, sucralfate, the inhibitor of phosphate absorption nicotinamide, placebo, or usual care without binder. In 82 studies, treatment was evaluated among adults with CKD G5D treated with haemodialysis or peritoneal dialysis, while in 22 studies, treatment was evaluated among participants with CKD G2 to G5. The duration of study follow-up ranged from 8 weeks to 36 months (median 3.7 months). The sample size ranged from 8 to 2103 participants (median 69). The mean age ranged between 42.6 and 68.9 years.Random sequence generation and allocation concealment were low risk in 25 and 15 studies, respectively. Twenty-seven studies reported low risk methods for blinding of participants, investigators, and outcome assessors. Thirty-one studies were at low risk of attrition bias and 69 studies were at low risk of selective reporting bias.In CKD G2 to G5, compared with placebo or usual care, sevelamer, lanthanum, iron and calcium-based phosphate binders had uncertain or inestimable effects on death (all causes), cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. Sevelamer may lead to constipation (RR 6.92, CI 2.24 to 21.4; low certainty) and lanthanum (RR 2.98, CI 1.21 to 7.30, moderate certainty) and iron-based binders (RR 2.66, CI 1.15 to 6.12, moderate certainty) probably increased constipation compared with placebo or usual care. Lanthanum may result in vomiting (RR 3.72, CI 1.36 to 10.18, low certainty). Iron-based binders probably result in diarrhoea (RR 2.81, CI 1.18 to 6.68, high certainty), while the risks of other adverse events for all binders were uncertain.In CKD G5D sevelamer may lead to lower death (all causes) (RR 0.53, CI 0.30 to 0.91, low certainty) and induce less hypercalcaemia (RR 0.30, CI 0.20 to 0.43, low certainty) when compared with calcium-based binders, and has uncertain or inestimable effects on cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. The finding of lower death with sevelamer compared with calcium was present when the analysis was restricted to studies at low risk of bias (RR 0.50, CI 0.32 to 0.77). In absolute terms, sevelamer may lower risk of death (all causes) from 210 per 1000 to 105 per 1000 over a follow-up of up to 36 months, compared to calcium-based binders. Compared with calcium-based binders, lanthanum had uncertain effects with respect to all-cause or cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification and probably had reduced risks of treatment-related hypercalcaemia (RR 0.16, CI 0.06 to 0.43, low certainty). There were no head-to-head studies of iron-based binders compared with calcium. The paucity of placebo-controlled studies in CKD G5D has led to uncertainty about the effects of phosphate binders on patient-important outcomes compared with placebo.It is uncertain whether the effects of binders on clinically-relevant outcomes were different for patients who were and were not treated with dialysis in subgroup analyses. AUTHORS' CONCLUSIONS: In studies of adults with CKD G5D treated with dialysis, sevelamer may lower death (all causes) compared to calcium-based binders and incur less treatment-related hypercalcaemia, while we found no clinically important benefits of any phosphate binder on cardiovascular death, myocardial infarction, stroke, fracture or coronary artery calcification. The effects of binders on patient-important outcomes compared to placebo are uncertain. In patients with CKD G2 to G5, the effects of sevelamer, lanthanum, and iron-based phosphate binders on cardiovascular, vascular calcification, and bone outcomes compared to placebo or usual care, are also uncertain and they may incur constipation, while iron-based binders may lead to diarrhoea.

Effect of Lanthanum Carbonate on All-Cause Mortality in Patients Receiving Maintenance Hemodialysis: a Meta-Analysis of Randomized Controlled Trials.

BACKGROUND/AIMS: Hyperphosphatemia is common in patients on hemodialysis. The efficacy of lanthanum carbonate (LC) in the treatment of hyperphosphatemia in these patients remains controversial. The objective of this meta-analysis was to evaluate the effect of LC on all-cause mortality in patients on maintenance hemodialysis. METHODS: We electronically searched the PubMed, EMBASE, and Cochrane Library databases for all randomized controlled trials (RCTs) comparing LC with other phosphate binders used in adult hemodialysis patients, including calcium carbonate, calcium acetate, and sevelamer. RESULTS: Nine RCTs involving 2813 patients were suitable for inclusion. Our results showed that all-cause mortality was significantly lower in patients who received LC than in those who received standard therapy (odds ratio [OR]: 0.45, 95% confidence interval [CI]: 0.32-0.63, P<0.00001). Compared with the controls, patients who received LC had significantly lower serum calcium and higher serum intact parathyroid hormone levels. However, there was no significant difference between the groups in the cardiovascular event rate (OR: 0.58, 95% CI: 0.31-1.06, P=0.07) or in serum phosphorus levels. CONCLUSION: Compared with standard therapy, LC reduced all-cause mortality in patients on hemodialysis but did not decrease the risk of cardiovascular events. The decrease in serum phosphorus level was similar between LC and the other phosphate binders, but the risk of hypercalcemia was lower in patients who received LC.

Phosphate-Binder Use in US Dialysis Patients: Prevalence, Costs, Evidence, and Policies.

Medicare costs for phosphate binders for US dialysis patients and patients with chronic kidney disease enrolled in Medicare Part D exceeded $1.5 billion in 2015. Previous data have shown that Part D costs for mineral and bone disorder medications increased faster than costs for all Part D medications for dialysis patients. Despite extensive use of phosphate binders and escalating costs, conclusive evidence is lacking that they improve important clinical end points in dialysis patients or non-dialysis-dependent patients with chronic kidney disease. Using dialysis patient data from the US Renal Data System and laboratory information from the Centers for Medicare & Medicaid Services (CMS) CROWNWeb data, we update information on trends in phosphate-binder use, calcium and phosphorus values, and costs for Medicare-covered dialysis patients. We discuss these results in the context of evidence from clinical trials, meta-analyses, and observational studies evaluating phosphate-binder efficacy, safety, comparative effectiveness, and cost-effectiveness. Based on our analysis, we note a need for US Food and Drug Administration guidance regarding clinical evaluation of new phosphate binders, and we suggest that it would be in CMS' best interest to fund a clinical trial to assess whether lower versus higher phosphate concentrations improve hard clinical outcomes, and if so, whether particular phosphate binders are superior to placebo or other binders in improving these outcomes.

Effect of high-protein meals during hemodialysis combined with lanthanum carbonate in hypoalbuminemic dialysis patients: findings from the FrEDI randomized controlled trial.

BACKGROUND: Inadequate protein intake and hypoalbuminemia, indicators of protein-energy wasting, are among the strongest mortality predictors in hemodialysis patients. Hemodialysis patients are frequently counseled on dietary phosphorus restriction, which may inadvertently lead to decreased protein intake. We hypothesized that, in hypoalbuminemic hemodialysis patients, provision of high-protein meals during hemodialysis combined with a potent phosphorus binder increases serum albumin without raising phosphorus levels. METHODS: We conducted a randomized controlled trial in 110 adults undergoing thrice-weekly hemodialysis with serum albumin <4.0 g/dL recruited between July 2010 and October 2011 from eight Southern California dialysis units. Patients were randomly assigned to receive high-protein (50-55 g) meals during dialysis, providing 400-500 mg phosphorus, combined with lanthanum carbonate versus low-protein (<1 g) meals during dialysis, providing <20 mg phosphorus. Prescribed nonlanthanum phosphorus binders were continued over an 8-week period. The primary composite outcome was a rise in serum albumin of ≥0.2 g/dL while maintaining phosphorus between 3.5-<5.5 mg/dL. Secondary outcomes included achievement of the primary outcome's individual endpoints and changes in mineral and bone disease and inflammatory markers. RESULTS: Among 106 participants who satisfied the trial entrance criteria, 27% ( n = 15) and 12% ( n = 6) of patients in the high-protein versus low-protein hemodialysis meal groups, respectively, achieved the primary outcome (intention-to-treat P-value = 0.045). A lower proportion of patients in the high-protein versus low-protein intake groups experienced a meaningful rise in interleukin-6 levels: 9% versus 31%, respectively (P = 0.009). No serious adverse events were observed. CONCLUSION: In hypoalbuminemic hemodialysis patients, high-protein meals during dialysis combined with lanthanum carbonate are safe and increase serum albumin while controlling phosphorus.

Inhibitory Effects of Lanthanum Chloride on Wear Particle-Induced Osteolysis in a Mouse Calvarial Model.

Osteolysis is a bone disorder associated with progressive destruction of bone tissues. However, the effects of lanthanum chloride (LaCl3) on osteolysis remain unknown. Therefore, the aim of this study was to determine the effects of LaCl3 on osteolysis in vivo. In a mouse calvarial model, C57BL/6J mice were injected with wear particles with or without LaCl3. Microcomputed tomography, hematoxylin and eosin staining, and tartrate-resistant acid phosphatase staining were performed for the pathological characterization of calvariae, and eight calvariae per group were prepared for the assay of TNF-α, IL-1ß, and RANKL secretion using quantitative enzyme-linked immunosorbent assay (ELISA). In mice treated with high-dose LaCl3, particle-induced osteolysis and inflammatory reaction were reduced compared with that in the vehicle-treated control. Moreover, treatment with high-dose LaCl3 suppressed the wear particle-induced decrease in bone mineral content, bone mineral density, and bone volume fraction. Bone destruction and resorption were higher in the LaCl3-treated group than in the saline-treated group but lower than those in the wear particle group. Finally, our results showed that treatment with a high dose of LaCl3 suppressed osteoclastogenesis. Thus, LaCl3 may represent a novel therapeutic agent for the treatment or prevention of wear particle-induced osteolysis and aseptic loosening.

Efficacy and safety of lanthanum carbonate versus calcium-based phosphate binders in patients with chronic kidney disease: a systematic review and meta-analysis.

PURPOSE: We conducted this review to assess the relative efficacy and safety of lanthanum carbonate versus calcium-based phosphate binders in chronic kidney disease. METHODS: We systematically searched PubMed, EMBASE, the Cochrane Controlled Trial Register of Controlled Trials and Chinese Biological Medical Database for randomized controlled trials comparing lanthanum carbonate with calcium-based phosphate binders in adult patients with chronic kidney disease. Study quality was assessed using the criteria outlined in the Cochrane Handbook for Systematic Reviews of intervention. Meta-analysis was conducted by reviewer manager software, version 5.3. RESULTS: Eleven trials with 1,501 participants were included. Lanthanum carbonate appeared to be associated with a significant reduction in progression of vascular calcification and a beneficial effect on bone outcomes without aluminum-like toxicity. Lanthanum carbonate achieved similar proportions of phosphate-controlled patients (RR 0.63, 95% CI 0.27-1.44) with lower incidence of hypercalcemia (RR 0.13, 95% CI 0.05-0.35) in comparison with calcium-based phosphate binders. Lanthanum carbonate was associated with significantly lower serum calcium, similar serum Ca × P product and higher serum iPTH compared with calcium salts in patients with chronic kidney disease. CONCLUSION: Lanthanum carbonate could delay the progression of vascular calcification and benefit chronic kidney disease patients on bone outcomes. Lanthanum carbonate could achieve similar proportion of phosphate-controlled patients as calcium-based phosphate binders with lower incidence of hypercalcemia.

Survival advantage of lanthanum carbonate for hemodialysis patients with uncontrolled hyperphosphatemia.

BACKGROUND: Lanthanum carbonate is a non-calcium phosphate binder that is effective for the treatment of hyperphosphatemia. However, it is unknown whether treatment with lanthanum affects survival. METHODS: We retrospectively collected data on maintenance hemodialysis patients at 22 facilities (n = 2292) beginning in December 2008, a time point immediately prior to the commercial availability of lanthanum in Japan. We compared 3-year all-cause mortality among patients who initiated lanthanum (n = 560) and those who were not treated with lanthanum during the study period (n = 560) matched by the propensity score of receiving lanthanum. Several sensitivity analyses were performed to test the robustness of the primary analysis. RESULTS: After the market introduction of lanthanum, the percentage of patients receiving the binder increased gradually to 27%. In the propensity score-matched analysis, the mortality rate for the lanthanum group was not significantly lower than the non-lanthanum group [hazard ratio (HR), 0.71; 95% confidence interval (CI), 0.47-1.09). However, stratification by serum phosphorus disclosed significant survival benefit of lanthanum for patients with serum phosphorus >6.0 mg/dL (HR, 0.52; 95% CI, 0.28-0.95), but not in patients with serum phosphorus ≤6.0 mg/dL (HR, 1.00; 95% CI, 0.55-1.84). The survival benefit of lanthanum in patients with serum phosphorus >6.0 mg/dL was consistent across subgroups and robust in different analytical approaches. CONCLUSIONS: Treatment with lanthanum was independently associated with a significant survival benefit in hemodialysis patients with inadequately controlled hyperphosphatemia. Further studies are required to confirm these findings.

Effect of lanthanum carbonate versus calcium-based phosphate binders in dialysis patients: a meta-analysis.

BACKGROUND: The effects of lanthanum carbonate (LC) vs. calciumbased phosphate binders in dialysis patients have been a matter of debate. METHODS: We electronically searched PubMed, Embase, CENTRAL, and CBM for all randomized controlled trials comparing LC with calcium-based phosphate binders in adult dialysis patients. Quality assessment was performed using the Cochrane risk of bias tool. Metaanalysis was conducted by RevMan 5.2. RESULTS: Nine studies were eligible for our meta-analysis. There was no significant difference in all-cause mortality (RR 0.84, 95% CI 0.25 - 2.83) and cardiovascular events (RR 0.84, 95% CI 0.55 - 1.29) between LC and calcium-based phosphate binders. LC was associated with similar proportions of phosphate-controlled patients (RR 0.63, 95% CI 0.27 - 1.44) and lower incidence of hypercalcemia (RR 0.13, 95% CI 0.05 - 0.35) in comparison to calcium-based phosphate binders. Compared with calcium salts, LC was associated with significantly lower serum calcium, similar serum Ca x P product and higher serum iPTH. CONCLUSION: Despite the trends observed, we found no statistically significant differences in all-cause mortality and cardiovascular events between LC and calcium-based phosphate binders in dialysis patients. The conclusion was limited by lack of large sample and long-term trials. LC could reduce the incidence of hypercalcemia while comparable with calcium-based phosphate binders in reducing serum phosphorus level.

Estudio REFOS: eficacia y seguridad del carbonato de lantano en la práctica clínica en España / REFOS study: Efficacy and safety of Lanthanum Carbonate in clinical practice in Spain

El carbonato de lantano es un potente captor de fósforo que en ensayos clínicos ha mostrado eficacia y seguridad para el manejo de la hiperfosforemia, aunque existen pocos datos en la práctica clínica habitual. El objetivo del estudio fue evaluar, en la práctica clínica habitual, su eficacia y seguridad en pacientes en diálisis. Se recogieron, retrospectivamente, datos de 15 meses de seguimiento, correspondientes a los 3 meses previos al inicio del tratamiento con carbonato de lantano y 12 meses después del inicio. Los datos incluían valores séricos de calcio, fósforo, fosfatasa alcalina, PTH, enzimas hepáticas y hemograma, así como la dosis diaria prescrita de carbonato de lantano, la medicación concomitante, el cumplimiento terapéutico y los eventos adversos. Se incluyeron 674 pacientes, de los cuales completaron el estudio 522. Los abandonos se debieron en mayor medida a trastornos gastrointestinales (26 %) e hipofosfatemia (19 %). El fósforo sérico disminuyó de 6,4 ± 1,7 mg/dl (inicio) a 4,9 ± 1,4 mg/dl (12 meses) (p < 0,001). Al final del seguimiento el 47 % se encontraba dentro del rango de fósforo deseado (3,5-5 mg/dl). No hubo variaciones significativas en el resto de los parámetros. Dosis inicial de carbonato de lantano: 1900 mg/día, y dosis final: 2300 mg/día. Las variables que se asociaron de forma independiente con la fosforemia final fueron el fósforo sérico basal y el cumplimiento terapéutico. Respecto a la seguridad, se observaron 238 efectos adversos leves o moderados que ocurrieron en 117 pacientes, estando el 88 % relacionado con alteraciones gastrointestinales. En conclusión, el carbonato de lantano reduce los valores séricos de fósforo en pacientes en diálisis con un buen perfil de seguridad y aceptable adherencia a este, siendo los trastornos gastrointestinales el efecto adverso más frecuente (AU)

Lanthanum carbonate is a powerful phosphate binder that has shown efficacy and safety in clinical trials for hyperphosphataemia management, although there are few data in regular clinical practice. The study's objective was to evaluate, in regular clinical practice, its efficacy and safety in patients on dialysis. We retrospectively collected data from 15 months of monitoring, corresponding to 3 months prior to the start of treatment with lanthanum carbonate until 12 months after the start. Results included values of serum calcium, phosphorus, alkaline phosphatase, iPTH, hepatic enzymes and haemogram, as well as the daily-prescribed dose of lanthanum carbonate, the concomitant medication, treatment compliance and adverse events. 647 patients were included of which 522 completed the study. Abandonment, for the most part, was due to gastrointestinal disorders (26%) and hypophosphatemia (19%). Serum phosphorus decreased from 6.4 ± 1.7mg/dl (start) to 4.9 ± 1.4mg/dl (12 months) (P<.001). At the end of the monitoring period, 47% were within the desired phosphorus range (3.5-5mg/dl). There were no significant variations in the remaining parameters. Initial dose of lanthanum carbonate: 1900mg/day; and end dose: 2300mg/day. The variables independently associated with phosphataemia were baseline serum phosphorus and treatment compliance. In relation to safety, we observed 238 slight or moderate adverse effects in 117 patients, with 88% linked to gastrointestinal abnormalities. In conclusion, lanthanum carbonate reduces the serum phosphorus values in patients on dialysis with a good safety profile and acceptable adherence to that profile, with gastrointestinal disorders being the most frequent adverse effect (AU)

Multicenter study on the long-term (3-year) efficacy of lanthanum carbonate in dialysis patients.

We previously conducted a multicenter study enrolling 101 dialysis patients with hyperphosphatemia in which lanthanum carbonate (LC) was administered for 2 years. In this study, the administration has been continued for an additional year, and we have evaluated the long-term (a total of 3 years) effects of LC. The average serum phosphorus (P) level was 6.05 mg/dL at the start and decreased to 5.84 mg/dL after 3 years, but no significant differences were observed at both points. The average serum corrected calcium (Ca) level significantly reduced after 3 years (P < 0.001). As results of evaluating the achievement rates with the management target values of serum P, Ca and intact parathyroid hormone (PTH) stated in the Japanese guideline, the achievement rates increased after 3 years. From these results, LC is considered to be a useful P binder that can be used for long-term treatment of hyperphosphatemia, without causing a Ca load.

Clinical effects of long-term (36-month) lanthanum carbonate administration in hemodialysis patients in Japan.

In this study, we investigated the clinical effects of long-term administration of the phosphorus (P) binder lanthanum carbonate (LC), which was launched in Japan in 2009. The subjects were 58 dialysis patients who began receiving LC, and we evaluated the clinical effects for up to 36 months after treatment initiation. The average serum P concentration remained low during the 36-month study period, with a significant reduction from 6.25 mg/dL at the start of the study to 4.94 mg/dL after 36 months (P < 0.001). A significant reduction was also observed in the average serum calcium concentration after 36 months (P < 0.05), but not in the serum intact parathyroid hormone concentration. Significant reductions were also observed in the average serum total protein, albumin and potassium concentrations (P < 0.05). The dosages of LC increased by approximately 1.9-fold after 36 months, in contrast, the dosages of concomitantly used sevelamer hydrochloride and Ca carbonate preparations decreased. These results indicate that LC could be used to treat hyperphosphatemia without causing hypercalcemia, and would be useful for long-term treatment with hemodialysis patients.

Increase in the dosage amount of vitamin D3 preparations by switching from calcium carbonate to lanthanum carbonate.

It is widely known that dialysis patients who are administered vitamin D preparations have a better prognosis than patients who are not. In this study, of 22 patients on maintenance dialysis who had been administered calcium (Ca) carbonate in our hospital, we investigated the dosage amount of vitamin D3 preparations after the phosphorus (P) binder was switched from Ca carbonate to the newly developed lanthanum carbonate (LC). After completely switching to LC, the dosage amount of oral vitamin D3 preparation (alfacalcidol equivalent) was significantly increased from 0.094 µg/day to 0.375 µg/day (P = 0.0090). No significant changes were observed in the values of serum corrected Ca, alkaline phosphatase, intact parathyroid hormone and P after switching. The administration of LC enabled complete cessation of the administration of Ca carbonate preparations, and increased the dosage amount of vitamin D3 preparations. Therefore, LC may be a useful P binder to improve patient prognosis.

Changes in fibroblast growth factor 23 levels in normophosphatemic patients with chronic kidney disease stage 3 treated with lanthanum carbonate: results of the PREFECT study, a phase 2a, double blind, randomized, placebo-controlled trial.

BACKGROUND: High levels of circulating fibroblast growth factor 23 (FGF23) are associated with chronic kidney disease (CKD) progression and high mortality. In the Phosphate Reduction Evaluation of FGF23 in Early CKD Treatment (PREFECT) study, we assessed the effect of reducing intestinal phosphate absorption using lanthanum carbonate on FGF23 levels in normophosphatemic patients with CKD stage 3. METHODS: Thirty-five individuals were randomized to lanthanum carbonate 3000 mg/day (n=23) or placebo (n=12) for 12 weeks. Levels of intact FGF23 (iFGF23), C-terminal FGF23, serum and urinary phosphate and calcium, intact parathyroid hormone and 1,25-dihydroxyvitamin D were assessed. RESULTS: The median age was 65 years in the lanthanum group and 73 years in the placebo group; 58.8% and 41.7% were men, respectively. No significant difference was seen in mean iFGF23 between groups at week 12. There was, however, a transient reduction from baseline in iFGF23 in the lanthanum group at week 1, from 70.5 pg/ml to 51.9 pg/ml, which was not seen in the placebo group; this between-group difference in percentage change from baseline was significant in post hoc analyses (p=0.0102). Urinary phosphate decreased after 1 week of lanthanum treatment and remained low at week 12. CONCLUSIONS: Reducing intestinal phosphate absorption with lanthanum carbonate did not lead to sustained reductions in iFGF23 in patients with CKD stage 3, although phosphaturia decreased. This suggests that factors other than phosphate burden may be responsible for driving increases in circulating FGF23 in patients with CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01128179, 20 May 2010.