title: Abnormal mineral metabolism and mortality in hemodialysis patients with secondary hyperparathyroidism: evidence from marginal structural models used to adjust for time-dependent confounding.
abstract: BACKGROUND
  Hemodialysis patients with mineral and bone disorders (MBDs) have an abnormally high relative risk of death, but their absolute risk of death is unknown. Further, previous studies have not accounted for possible time-dependent confounding of the association between MBD markers and death due to the effect of markers of MBD on treatments, which subsequently may affect MBD markers.
  
  
  METHODS
  Multicenter, 3-year, prospective, case-cohort study.
  
  
  METHODS
  8,229 hemodialysis patients with secondary hyperparathyroidism (parathyroid hormone level ≥180 pg/mL and/or receiving vitamin D receptor activators) at 86 facilities in Japan.
  
  
  METHODS
  Serum phosphorus, calcium, and parathyroid hormone levels.
  
  
  RESULTS
  All-cause mortality.
  
  
  METHODS
  Marginal structural models were used to compute absolute differences in all-cause mortality associated with different levels of predictors while accounting for time-dependent confounding.
  
  
  RESULTS
  The association between phosphorus level and mortality appeared U-shaped, although only higher phosphorus level categories reached statistical significance: compared to those with phosphorus levels of 5.0-5.9 mg/dL (1.61-1.93 mmol/L), patients with the highest (≥9.0 mg/dL [≥2.90 mmol/L]) phosphorus levels had 9.4 excess deaths/100 person-years (rate ratio, 2.79 [95% CI, 1.26-6.15]), whereas no association was found for the lowest phosphorus category (<3.0 mg/dL [<0.97 mmol/L]; rate ratio, 1.54 [95% CI, 0.87-2.71]). Similarly, hypercalcemia (≥10.0 mg/dL [≥2.50 mmol/L]) was associated with excess deaths, and the highest level of hypercalcemia (≥11.0 mg/dL [≥2.75 mmol/L]) was associated with 5.8 excess deaths/100 person-years (rate ratio, 2.38 [95% CI, 1.77-3.21]) compared to those with levels of 9.0-9.4 mg/dL (2.25-2.37 mmol/L). Abnormally high parathyroid hormone levels were not associated with excess deaths.
  
  
  CONCLUSIONS
  Possible residual confounding.
  
  
  CONCLUSIONS
  These results reinforce the idea that serum calcium (in addition to phosphorus) level is an important predictor of the absolute risk of death in hemodialysis patients with secondary hyperparathyroidism.
authors.affiliation: Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Fukagawa
authors.affiliation: Institute for Health Outcomes and Process Evaluation Research (iHope International), Kyoto and Tokyo, Japan; Department of Healthcare Epidemiology, School of Public Health, Kyoto University Faculty of Medicine, Kyoto, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Kido
authors.affiliation: Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Komaba
authors.affiliation: Institute for Health Outcomes and Process Evaluation Research (iHope International), Kyoto and Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Onishi
authors.affiliation: Institute for Health Outcomes and Process Evaluation Research (iHope International), Kyoto and Tokyo, Japan; Division of Biostatistics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takuhiro
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Institute for Health Outcomes and Process Evaluation Research (iHope International), Kyoto and Tokyo, Japan; Division of Nephrology, Showa University School of Medicine, Tokyo, Japan; Center for Innovative Research for Communities and Clinical Excellence, Fukushima Medical University, Fukushima, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Institute for Health Outcomes and Process Evaluation Research (iHope International), Kyoto and Tokyo, Japan; Department of Healthcare Epidemiology, School of Public Health, Kyoto University Faculty of Medicine, Kyoto, Japan; Center for Innovative Research for Communities and Clinical Excellence, Fukushima Medical University, Fukushima, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kurita
authors.affiliation: Institute for Health Outcomes and Process Evaluation Research (iHope International), Kyoto and Tokyo, Japan; Department of Healthcare Epidemiology, School of Public Health, Kyoto University Faculty of Medicine, Kyoto, Japan; Center for Innovative Research for Communities and Clinical Excellence, Fukushima Medical University, Fukushima, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Fukuma
authors.affiliation: Division of Nephrology, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Akizawa
authors.affiliation: Institute for Health Outcomes and Process Evaluation Research (iHope International), Kyoto and Tokyo, Japan; Department of Healthcare Epidemiology, School of Public Health, Kyoto University Faculty of Medicine, Kyoto, Japan; Center for Innovative Research for Communities and Clinical Excellence, Fukushima Medical University, Fukushima, Japan. Electronic address: fukuhara.shunichi.6m@kyoto-u.ac.jp.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Fukuhara
mesh_terms: D000368:Aged; D002118:Calcium / Q000097:blood*; D015986:Confounding Factors, Epidemiologic; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000453:epidemiology*; D006962:Hyperparathyroidism, Secondary / Q000453:epidemiology / Q000378:metabolism* / Q000401:mortality*; D007676:Kidney Failure, Chronic / Q000453:epidemiology / Q000378:metabolism* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010281:Parathyroid Hormone / Q000097:blood*; D010758:Phosphorus / Q000097:blood*; D006435:Renal Dialysis / Q000401:mortality*; D018570:Risk Assessment; D016019:Survival Analysis
chemical_list: D010281:Parathyroid Hormone; D010758:Phosphorus; D002118:Calcium
keywords: Calcium; clinical epidemiology; death; end-stage renal disease; hemodialysis; hyperparathyroidism; hyperphosphatemia; mineral metabolism; parathyroid hormone (PTH)