title: Cystatin C and long term risk of community-acquired sepsis: a population-based cohort study.
abstract: BACKGROUND
  Chronic kidney disease (CKD) and systemic inflammation are risk factors for sepsis. While often viewed as a marker of chronic kidney disease, Cystatin C (Cyst-C) may also reflect systemic inflammation. We sought to determine the association between elevated baseline Cyst-C and long-term rates of community-acquired sepsis, and to determine if this relationship is influenced by traditional markers of CKD (estimated glomerular filtration rate [eGFR], albumin-to-creatinine ratio [ACR]) and inflammation (high sensitivity C-reactive protein [hsCRP]).
  
  
  METHODS
  We studied 30,239 adults ≥45 years old from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. The primary exposure was elevated Cyst-C (>1.12 mg/dL) measured at study baseline. The primary outcome was the first sepsis hospitalization during a 10-year observation period. Using Cox regression, we evaluated the association between elevated Cyst-C and first sepsis event, adjusted for sociodemographics, health behaviors, chronic medical conditions, eGFR, ACR and hsCRP.
  
  
  RESULTS
  Among participants, 1,532 experienced a sepsis event. Median Cyst-C levels were: sepsis 1.08 (IQR 0.91-1.33) mg/dL (43.8% >1.12 mg/dL), non-sepsis 0.94 (IQR 0.82-1.10) mg/dL (23.4% >1.12 mg/dL). Cyst-C > 1.12 mg/dL was independently associated with increased rates of sepsis, adjusted for participant demographics, health behaviors and chronic medical conditions (HR 1.75; 95% CI: 1.55-1.96). The addition of eGFR < 60 mg/min/1.73 m(2,) ACR ≥ 30 mg/g and hsCRP > 3.0 mg/dL only partially attenuated the association between Cyst-C > 1.12 mg/dL and rates of sepsis (adjusted HR 1.51; 1.32-1.72).
  
  
  CONCLUSIONS
  Elevated Cyst-C is associated with increased long-term rates of community-acquired sepsis, independent of abnormal eGFR, ACR or hsCRP. Cyst-C may play a role in long-term sepsis risk prediction and prevention.
authors.affiliation: Department of Emergency Medicine, University of Alabama School of Medicine, 619 19th Street South, OHB 251, Birmingham, AL, 35249, USA. powelltc@uab.edu.
authors.forename: Thomas Clark
authors.initials: TC
authors.lastname: Powell
authors.affiliation: Department of Emergency Medicine, University of Alabama School of Medicine, 619 19th Street South, OHB 251, Birmingham, AL, 35249, USA. johndonnelly@uabmc.edu.|Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA. johndonnelly@uabmc.edu.|Division of Preventive Medicine, Department of Medicine, University of Alabama School of Medicine, Birmingham, Alabama, USA. johndonnelly@uabmc.edu.
authors.forename: John P
authors.initials: JP
authors.lastname: Donnelly
authors.affiliation: Division of Nephrology, Department of Medicine, University of Alabama School of Medicine, Birmingham, Alabama, USA. ogutierrez@uabmc.edu.|Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA. ogutierrez@uabmc.edu.
authors.forename: Orlando M
authors.initials: OM
authors.lastname: Gutiérrez
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA. russellg@uab.edu.
authors.forename: Russell L
authors.initials: RL
authors.lastname: Griffin
authors.affiliation: Division of Preventive Medicine, Department of Medicine, University of Alabama School of Medicine, Birmingham, Alabama, USA. msafford@uab.edu.
authors.forename: Monika M
authors.initials: MM
authors.lastname: Safford
authors.affiliation: Department of Emergency Medicine, University of Alabama School of Medicine, 619 19th Street South, OHB 251, Birmingham, AL, 35249, USA. hwang@uabmc.edu.
authors.forename: Henry E
authors.initials: HE
authors.lastname: Wang
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D015331:Cohort Studies; D017714:Community-Acquired Infections / Q000453:epidemiology* / Q000378:metabolism; D003404:Creatinine / Q000378:metabolism; D055316:Cystatin C / Q000378:metabolism*; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007249:Inflammation; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011014:Pneumonia / Q000453:epidemiology* / Q000378:metabolism; D016016:Proportional Hazards Models; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000378:metabolism; D012307:Risk Factors; D018805:Sepsis / Q000453:epidemiology* / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D014552:Urinary Tract Infections / Q000453:epidemiology* / Q000378:metabolism
chemical_list: D015415:Biomarkers; C525030:CST3 protein, human; D055316:Cystatin C; D012709:Serum Albumin; D002097:C-Reactive Protein; D003404:Creatinine