| Chronic kidney disease is a serious public health problem that threatens the health of the patients and brought a heavy burden to the patients and society. The incidence of chronic kidney disease is as high as200cases per million per year in many countries and nearing400cases per million per year in the USA, Taiwan, and some regions in Mexico. Hyperphosphatemia is a universal complication in patients with chronic kidney disease when the glomerular filtration rate falls below25ml/min. The long-term consequences of inadequate phosphorus control include hyperparathyroidism, metabolic bone disease and cardiovascular calcification. Recently, epidemiological data showed that hyperphosphatemia is associated with increased overall mortality, morbidity of cardiovascular disease, hospitalization in hemodialysis patients, reduced quality life of the patients and increased economical burden. The Kidney Disease Outcomes Quality Initiative (KDOQI) in the USA have recommended serum phosphorus targets of2.7-4.6mg/dL in CKD stages3-5, and3.5-5.5mg/dL in CKD stage5D. Phosphate binders are usually required by the majority of patients suffering from hyperphosphatemia because of the inadequate control of serum phosphate levels by dietary restriction and dialysis.Aluminum-based phosphate binders, widely used in the1970s, although highly effective, have been associated with osteomalacia, microcytic anemia, arthropathy, and encephalopathy due to aluminum accumulation. Thus, if prescribed in very restricted circumstances, aluminum should be used only for4-8weeks. Calcium-based phosphate binders, while moderately effective and inexpensive, have been used as the first line therapy. However, these agents can produce elevated serum calcium concentrations in up to60%of patients, associated with hypercalcemia, soft tissue and cardiovascular calcification, suppression of parathyroid gland and adynamic bone disease. Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend restricting the use of calcium-based phosphate binders in patients with persistent or recurrent hypercalcemia or arterial calcification, or both. Sevelamer, a calcium-and metal-free synthetic phosphate-binding agent, is a nonabsorbed cationic polymer that binds phosphate anions through ion exchange and hydrogen binding in the duodenum. Sevelamer has been shown also to have a number of other beneficial effects, including reductions in serum low density lipoprotein-cholesterol and inflammatory makers. But it is associated with metabolic acidosis, gastrointestinal disorders and high pill burden.Lanthanum, a rare earth element, discovered in1839by Mosander, has a high affinity for phosphate and a low oral bioavailability. Its oral administration effectively decreases phosphate absorption from the gastrointestinal tract by the formation and excretion of highly insoluble complexes with phosphate in foods. Excretion of the small absorbed fraction is predominantly via bile, ensuring that the pharmacokinetics of lanthanum are similar in healthy humans and chronic kidney disease patients. Treatment with lanthanum carbonate is not associated with hypercalcemia and studies have confirmed the safety and efficacy of lanthanum carbonate up to6years of treatment.Differences between phosphate binders exist with respect to the clinical efficacy, possible side-effect profiles, as well as market prices. We conducted this review to assess the relative effect and safety of lanthanum carbonate versus placebo, calcium-based phosphate binders and sevelamer in patients with CKD. The study is divided into three parts:PART IEffect and safety of lanthanum carbonate versus placebo for hyperphosphatemia in patients with chronic kidney disease ObjectiveTo assess the effect and safety of lanthanum carbonate versus placebo in adult patients with chronic kidney disease.MethodsWe electronically searched MEDLINE, EMBASE, CENTRAL and CBM for randomized controlled trials about lanthanum carbonate versus placebo 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 RevMan5.3.Results1. Only one study reported deaths in the study duration, there was no significant difference in all-cause mortality between lanthanum carbonate and placebo (OR:1.67,95%CI0.06-44.05, p=0.76).2. There was no significant difference on vascular stiffness or calcification between lanthanum carbonate and placebo.3. The proportions of phosphate-controlled patients were higher in lanthanum carbonate group than that in placeo group (OR:8.92,95%CI3.91--20.35, p<0.00001).4. Compared with placebo, lanthanum carbonate was associated with lower serum phosphorus (SMD:-1.15mg/dL,95%CI-1.70--0.59, p<0.0001) and calcium phosphorus product levels (SMD:-0.76mg2/dL2,95%CI-1.13--0.39, p<0.0001), similar serum calcium (SMD:0.50mg/dL,95%CI-0.26-1.26, p=0.20), iPTH (SMD:0.13pg/mL,95%CI-0.30-0.56, p=0.55) and FGF-23levels(SMD:-14.43pg/mL,95%CI-35.45-6.59, p=0.18).5. Serum lanthanum was higher in lanthanum carbonate in comparison to placeo (MD:0.49ng/mL,95%CI0.37-0.62, p<0.00001).6. The incidence of nausea (OR:2.35,95%CI1.28-4.33, p=0.006) and vomitting (OR:2.88,95%CI1.45-5.71, p=0.002) was higher in lanthanum carbonate group compared with placebo. The incidece of diarrhea (OR:0.59,95% CI0.15-2.29, p=0.45), constipation (OR:1.70,95%CI0.54-5.32, p=0.36), abdominal pain (OR:1.46,95%CI0.34-6.32, p=0.62), hypotension (OR:1.18,95%CI0.36-3.83, p=0.79), myalgia (OR:0.48,95%CI0.22-1.07, p=0.07), pruritus (OR:0.45,95%CI0.03-7.10, p=0.57) and dialysis graft occlusion (OR:4.34,95%CI0.73-25.70, p=0.11) was similar between the two treatment groups. The incidence of hypocalcemia (OR:0.06,95%CI0.01-0.44, p=0.006) and dyspepsia (OR:0.27,95%CI0.09-0.82, p=0.02) was lower in lanthanum carbonate group in comparison to placebo.ConclusionsThere was no evidence that lanthanum carbonate could significantly reduce all-cause mortality, delay the progression of vascular calcification and improve bone mineral density in patients with chronic kidney disease. Compared with placebo, lanthanum carbonate effectively reduced serum phosphorus and calcium-phosphorus product levels, and did not affect the levels of serum calcium, iPTH and FGF-23. The incidence of nausea and vomiting was higher in lanthanum carbonate group, but in America, older people or non-dialysis patients, the incidence of nausea and vomiting was similar between the two groups. Lanthanum carbonate could reduce the incidence of hypocalcemia, dyspepsia and diarrhea in young or dialysis patients. There was a small amount of accumulation of lanthanum carbonate in the body, but the system toxicity have not yet been found. PART IIEffect and safety of lanthanum carbonate versus calcium-based phosphate binders for hyperphosphatemia in patients with chronic kidney disease ObjectiveTo assess the effect and safety of lanthanum carbonate versus calcium-based phosphate binders in adult patients with chronic kidney disease.MethodsWe electronically searched MEDLINE, EMBASE, CENTRAL and CBM for randomized controlled trials about lanthanum carbonate versus 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 RevMan5.3.Results1. There was no significant differece in all-cause mortality between lanthanum carbonate and calcium-based phosphate binders (OR:0.83,95%CI0.23-2.98, p=0.78).2. No significant difference was found in cardiovascular events between lanthanum carbonate and calcium-based phosphate binders (OR:0.84,95%CI0.52-1.33, p=0.43).3. Compared with calcium-based phosphate binders, lanthanum carbonate delayed the progression of the coronary artery or abdominal aortic calcification. But there was no significant difference in thoracic aortic calcification between the two groups.4. Compared with calcium phosphate binder, lanthanum carbonate reduced the incidence of low turnover bone disease, but has no obvious effect on bone mineral density.5. The incidence of hypercalcemia was lower in lanthanum carbonate group than calcium-based phosphate binders group (OR:0.09,95%CI0.03-0.24, p<0.00001).6. There was no significant difference in the proportions of phosphate controlled patients between lanthanum carbonate and calcium-based phosphate binders (OR:0.51,95%CI0.11-2.41, p=0.40). 7. Compared with calcium-based phosphate binders, lanthanum carbonate was associated with higher serum phosphorus (MD:0.21mg/dL,95%CI0.12-0.31, p<0.0001) and alkaline phosphatase levels (MD:9.32U/L,95%CI2.12-16.52, p=0.01), lower serum calcium (MD:-0.28mg/dL,95%CI-0.54--0.03, p=0.03) and similar calcium phosphorus product (SMD:-0.86mg2/dL2,95%CI-2.64-0.93, p=0.35).8. The incidence of nausea (OR:1.65,95%CI1.13-2.40, p=0.010) and vomitting (OR:2.79,95%CI1.07-7.27, p=0.04) was higher in lanthanum carbonate group compared with calcium-based phosphate binders. There was no significant difference in the incidence of diarrhea (OR:1.44,95%CI0.93-2.25, p=0.10), constipation (OR:0.74,95%CI0.47-1.16, p=0.19), dyspepsia (OR:1.06,95%CI0.18-6.38, p=0.95), abdominal discomfort (OR:0.89,95%CI0.31-2.62, p=0.84), hypotension (OR:0.79,95%CI0.48-1.30, p=0.36), rhinitis (OR:1.06,95%CI0.60-1.86, p=0.84), headache (OR:0.73,95%CI0.40-1.32, p=0.30) and cramps (OR:1.17,95%CI0.66-2.08, p=0.59) between the two groups.ConclusionsThere was no evidence that lanthanum carbonate could reduce all-cause mortality and cardiovascular events in patients with chronic kidney disease. Lanthanum carbonate could delay the progression of the coronary artery or abdominal aortic 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 relatively higher serum phosphorus levels. Compared with calcium-based phosphate binders, lanthanum carbonate reduced the incidence of hypercalcemia, and avoided over-suppression of iPTH secretion. The incidence of nausea and vomiting was higher in lanthanum carbonate group. But in Asia, old people or diabetic nephropathy patients, the incidence of nausea was simiar beween the two groups. PART IIIEffect and safety of lanthanum carbonate versus sevelamer for hyperphosphatemia in patients with chronic kidney diseaseObjectiveTo assess the effects and safety of lanthanum carbonate versus sevelamer in adult patients with chronic kidney disease.MethodsWe electronically searched MEDLINE, EMBASE, CENTRAL and CBM for randomized controlled trials about lanthanum carbonate versus sevelamer 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 RevMan5.3.Results1. Only one study reported deaths in the study duration, there was no significant difference in all-cause mortality between lanthanum carbonate and sevelamer (OR:3.07,95%CI0.12-77.59, p=0.50).2. Only one study reported the proportions of phosphate-controlled patients and found no significant difference in the proportions of phosphate-controlled patients between lanthanum carbonate and sevelamer (OR:3.56,95%CI0.89-14.28, p=0.07).3. Serum phosphorus was lower in lanthanum carbonate group than sevelamer group (MD:-0.30mg/dL,95%CI-0.32--0.28, p<0.00001). Compared with sevelamer, lanthanum carbonate was associated with similar serum calcium (MD:0.09mg/dL,95%CI-0.09-0.27, p=0.33) and iPTH (MD:9.23pg/mL,95%CI5.80-12.67, p<0.00001). Only one study reported serum calcium phosphorus product levels and found no signicicant difference between lanthanum carbonate and sevelamer (MD:-2.00mg2/dL2,95%CI-4.91-0.91, p=0.18).4. There was no significant difference in the incidence of all adverse reactions between lanthanum carbonate and sevelamer (OR:0.72,95%CI0.51-1.02, p=0.07). But the incidence of constipation was lower in lanthanum carbonate group in comparison to sevelamer (OR:0.21,95%CI0.07-0.67, p=0.008).ConclusionsLanthanum carbonate was superior to sevelamer in reducing serum phosphorus with lower incidence of constipation. The conclusion of the comparison between lanthanum carbonate and sevelamer in many outcomes could not be made due to the small number of included trials, and it needs more clinical trials to demonstrate. |
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