title: The survival advantage for haemodialysis patients taking vitamin D is questioned: findings from the Dialysis Outcomes and Practice Patterns Study.
abstract: BACKGROUND
  Retrospective studies of haemodialysis patients from large dialysis organizations in the United States have indicated that intravenous vitamin D may be associated with a survival benefit. However, patients prescribed vitamin D are generally healthier than those who are not, suggesting that treatment by indication may have biased previous findings. Additionally, no survival benefit associated with vitamin D has been shown in a recent meta-analysis in CKD patients. Because treatment-by-indication bias due to both measured and unmeasured confounders cannot be completely accounted for in standard regression or marginal structural models (MSMs), this study evaluates the association between vitamin D and mortality among participants in the Dialysis Outcomes and Practice Patterns Study (DOPPS) using standard regression and MSMs with an expanded set of covariates, as well as by instrumental variable models to minimize potential bias due to unmeasured confounders.
  
  
  METHODS
  Data from 38 066 DOPPS participants from 12 countries between 1996 and 2007 were analysed. Mortality risk was assessed using standard baseline and time-varying Cox regression models, adjusted for demographics and detailed comorbidities, and MSMs. In models similar to instrumental variable analysis, the facility percentage of patients prescribed vitamin D, adjusted for the patient case mix, was used to predict patient-level mortality.
  
  
  RESULTS
  Vitamin D prescription was significantly higher in the USA compared to other countries. On average, patients prescribed vitamin D had fewer comorbidities compared to those who were not. Vitamin D therapy was associated with lower mortality in adjusted time-varying standard regression models [relative ratio (RR) = 0.92 (95% confidence interval: 0.87-0.96)] and baseline MSMs [RR = 0.84 (0.78-0.98)] and time-varying MSMs [RR = 0.78 (0.73-0.84)]. No significant differences in mortality were observed in adjusted baseline standard regression models for patients with or without vitamin D prescription [RR = 0.98 (0.93-1.02)] or for patients in facility practices where vitamin D prescription was more frequent [RR for facilities in 75th versus 25th percentile of vitamin D prescription = 0.99 (0.94-1.04)].
  
  
  CONCLUSIONS
  Vitamin D was associated with a survival benefit in models prone to bias due to unmeasured confounding. In agreement with a meta-analysis of randomized controlled studies, no difference in mortality was observed in instrumental variable models that tend to be more independent of unmeasured confounding. These findings indicate that a randomized controlled trial of vitamin D and clinical outcomes in haemodialysis patients are needed and can be ethically conducted.
authors.affiliation: Department of Internal Medicine, Arbor Research Collaborative for Health, University of Michigan Health System, Ann Arbor, MI 48103, USA. francesca.tentori@ArborResearch.org
authors.forename: Francesca
authors.initials: F
authors.lastname: Tentori
authors.forename: Justin M
authors.initials: JM
authors.lastname: Albert
authors.forename: Eric W
authors.initials: EW
authors.lastname: Young
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Blayney
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Robinson
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Pisoni
authors.forename: Takashi
authors.initials: T
authors.lastname: Akiba
authors.forename: Roger N
authors.initials: RN
authors.lastname: Greenwood
authors.forename: Naoki
authors.initials: N
authors.lastname: Kimata
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Levin
authors.forename: Luis M
authors.initials: LM
authors.lastname: Piera
authors.forename: Rajiv
authors.initials: R
authors.lastname: Saran
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wolfe
authors.forename: Friedrich K
authors.initials: FK
authors.lastname: Port
mesh_terms: D000328:Adult; D000368:Aged; D002908:Chronic Disease; D015986:Confounding Factors, Epidemiologic; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000150:complications / Q000401:mortality* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D010818:Practice Patterns, Physicians'; D006435:Renal Dialysis; D012189:Retrospective Studies; D015983:Selection Bias; D015996:Survival Rate; D014807:Vitamin D / Q000627:therapeutic use*; D014815:Vitamins / Q000627:therapeutic use*
chemical_list: D014815:Vitamins; D014807:Vitamin D