title: Effects of different phosphate lowering strategies in patients with CKD on laboratory outcomes: A systematic review and NMA.
abstract: BACKGROUND
  Chronic kidney disease-mineral and bone disorder (CKD-MBD), a complication of chronic kidney disease, has been linked to reduced quality and length of life. High serum phosphate levels that result from CKD-MBD require phosphate-lowering agents, also known as phosphate binders. The objective of this systematic review is to compare the effects of available phosphate binders on laboratory outcomes in patients with CKD-MBD.
  
  
  METHODS
  Data sources included MEDLINE and EMBASE from January 1996 to April 2016, and the Cochrane Register of Controlled Trials up to April 2016. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstracted data and assessed risk of bias in eligible randomized controlled trials (RCTs). Eligible trials enrolled patients with CKD-MBD and randomized them to receive calcium-based phosphate binders (delivered as calcium acetate, calcium citrate or calcium carbonate), non-calcium-based phosphate binders (NCBPB) (sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, sucroferric oxyhydroxide and ferric citrate), phosphorus restricted diet (diet), placebo or no treatment and reported effects on serum levels of phosphate, calcium and parathyroid hormone. We performed Bayesian network meta-analyses (NMA) to calculate the effect estimates (mean differences) and 95% credible intervals for serum levels of phosphate, calcium and parathyroid hormone. We calculated direct, indirect and network meta-analysis estimates using random-effects models. We applied the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence for each pairwise comparison.
  
  
  RESULTS
  Our search yielded 1108 citations; 71 RCTs were retrieved for full review and 16 proved eligible. Including an additional 13 studies from a previous review, 29 studies that enrolled 8335 participants proved eligible; 26 trials provided data for quantitative synthesis. Sevelamer, lanthanum, calcium, iron, diet and combinations of active treatments (calcium or sevelamer or lanthanum and combination of calcium and sevelamer) resulted in significantly lower serum phosphate as compared to placebo (moderate to very low quality of evidence). We found no statistically significant differences between active treatment categories in lowering serum phosphate. Sevelamer, lanthanum and diet resulted in lower serum calcium compared to calcium (moderate quality evidence for lanthanum and diet; low quality evidence for Sevelamer). Iron, sevelamer and calcium yielded lower parathyroid hormone levels as compared to lanthanum. Meta-regression analyses did not yield a statistically significant association between treatment effect and trial duration.
  
  
  CONCLUSIONS
  We found few differences between treatments in impact on phosphate and differences in parathyroid hormone. Relative to calcium, sevelamer, lanthanum and diet showed significant reduction in serum calcium from baseline. Treatment recommendations should be based on impact on patient-important outcomes rather than on surrogate outcomes. Systematic review registration: PROSPERO CRD-42016032945.
authors.affiliation: Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Nigar
authors.identifier: http://orcid.org/0000-0001-6461-8801
authors.initials: N
authors.lastname: Sekercioglu
authors.affiliation: Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Argie
authors.initials: A
authors.lastname: Angeliki Veroniki
authors.affiliation: Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.|Department of Pediatrics and Anesthesia, McMaster University, Hamilton, Ontario, Canada.|Centre for Evaluation of Medicine, St Joseph's Healthcare-Hamilton, Hamilton, Ontario, Canada.|Biostatistics Unit, Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Hamilton, Ontario, Canada.|Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada.
authors.forename: Lehana
authors.initials: L
authors.lastname: Thabane
authors.affiliation: Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.|The Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada.|Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Busse
authors.affiliation: Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.|School of Nursing, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Noori
authors.initials: N
authors.lastname: Akhtar-Danesh
authors.affiliation: Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.|Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Iorio
authors.affiliation: Pharmaceutical Sciences Master Course, University of Sorocaba, UNISO, Sorocaba, Brazil.
authors.forename: Luciane
authors.initials: L
authors.lastname: Cruz Lopes
authors.affiliation: Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.|Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Gordon H
authors.initials: GH
authors.lastname: Guyatt
mesh_terms: D002118:Calcium / Q000097:blood*; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000097:blood* / Q000628:therapy*; D005260:Female; D006801:Humans; D008297:Male; D010281:Parathyroid Hormone / Q000097:blood*; D010710:Phosphates / Q000097:blood*
chemical_list: D010281:Parathyroid Hormone; D010710:Phosphates; D002118:Calcium