title: Association of serum chloride level with mortality and cardiovascular events in chronic kidney disease: the CKD-ROUTE study.
abstract: BACKGROUND
  Electrolyte abnormalities, particularly dysnatremia, are independent predictors of adverse outcome in individuals with and without renal failure. However, the association of serum chloride level (Cl-) with mortality or risk of cardiovascular (CV) events in chronic kidney disease (CKD) remains unclear.
  
  
  METHODS
  This prospective cohort study included 923 pre-dialysis CKD G2-G5 patients among the participants of the CKD Research of Outcomes in Treatment and Epidemiology (CKD-ROUTE) study, who newly visited 16 nephrology centers. The primary outcome was a composite of overall death and CV events, and the secondary outcome was overall death. Data were analyzed using the Cox hazards model with adjustment for potential confounders.
  
  
  RESULTS
  Median Cl-was 106.0 mEq/L at enrollment [quartile (Q) 1: ≤103.9, n =  207; Q2: 104.0-105.9, n =  207; Q3: 106.0-108.0, n =  289; Q4: ≥108.1, n = 220]. During a median follow-up of 33 months, there were 98 CV events, 66 deaths, and 154 composite outcomes. The hazard ratio (HR) for the composite outcome was higher for Q1 than Q3 [HR 1.72; 95 % confidence interval (CI) 1.08-2.72; P =  0.022]. As a continuous variable in a subset of patients whose Cl-was ≤106.0 mEq/L, higher Cl-was associated with lower risk of the composite outcome (HR 0.93; 95 % CI 0.87-0.99; P = 0.023). HR for all-cause mortality was also higher for Q1 than Q3 (HR 2.48; 95 % CI 1.22-5.03; P =  0.012).
  
  
  CONCLUSIONS
  Low Cl-was associated with increased mortality and risk of CV events in pre-dialysis CKD patients. Cl-may be an additional prognostic indicator in CKD.
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-8519, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Mandai
authors.affiliation: Department of Nephrology, Tokyo Kyosai Hospital, 2-3-8 Nakameguro, Meguro-ku, Tokyo, 153-8934, Japan. tokyo.kyosai.kanda@gmail.com.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Kanda
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-8519, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Iimori
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-8519, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Naito
authors.affiliation: Department of Nephrology, Nitobe Memorial Nakano General Hospital, 4-59-16 Chuo, Nakano, Tokyo, 164-0011, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Noda
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-8519, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: JA Toride Medical Center, 2-1-1 Hongo, Toride, Ibaraki, 302-0022, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Akazawa
authors.affiliation: Department of Nephrology, Tokyo Kyosai Hospital, 2-3-8 Nakameguro, Meguro-ku, Tokyo, 153-8934, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Oi
authors.affiliation: Department of Nephrology, Tsuchiura Kyodo General Hospital, 11-7 Manabeshinmachi, Tsuchiura, Ibaraki, 300-0053, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Toda
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-8519, Japan.
authors.forename: Eisei
authors.initials: E
authors.lastname: Sohara
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-8519, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Okado
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-8519, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-8519, Japan.
authors.forename: Tatemitsu
authors.initials: T
authors.lastname: Rai
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-8519, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis / Q000401:mortality*; D002423:Cause of Death; D016009:Chi-Square Distribution; D002712:Chlorides / Q000097:blood*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007564:Japan / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000175:diagnosis / Q000401:mortality*; D012307:Risk Factors; D013997:Time Factors
chemical_list: D015415:Biomarkers; D002712:Chlorides
keywords: Cardiovascular disease; Chloride; Chronic kidney disease; Electrolyte; Mortality; Sodium