title: Cardiac autonomic neuropathy and early progressive renal decline in patients with nonmacroalbuminuric type 1 diabetes.
abstract: OBJECTIVE
  Cardiac autonomic neuropathy predicts future adverse renal outcomes in the general population. This study sought to determine its relationship with early progressive renal decline in type 1 diabetes.
  
  
  METHODS
  A subset of participants with normoalbuminuria (n=204) or microalbuminuria (n=166) from the First Joslin Kidney Study underwent assessment for cardiac autonomic neuropathy using heart rate variability during baseline visits performed from January 1991 to April 1992. Cardiac autonomic neuropathy was defined as an R-R variation (mean circular resultant) <20. Participants also had baseline and follow-up measurement of eGFR. Early progressive renal decline was evaluated according to two definitions: early GFR loss (slope of eGFR estimated by cystatin C <-3.3%/year) and incident advanced CKD (stage ≥3, defined by eGFR [calculated by Modification of Diet in Renal Disease method] <60 ml/min per 1.73 m(2)). Association with baseline cardiac autonomic neuropathy was assessed by adjusted logistic regression and Cox proportional hazards.
  
  
  RESULTS
  Among the 370 participants, 47 (13%) had baseline cardiac autonomic neuropathy, 51 (14%) had early GFR loss, and 68 (18%) had incident advanced CKD over a median 14-year follow-up. Early GFR loss occurred in 15 (32%) of the 47 patients with baseline autonomic neuropathy and in 32 (10%) of the 323 without baseline autonomic neuropathy (P<0.001). Baseline autonomic neuropathy was strongly associated with odds of early GFR loss (adjusted odds ratio, 4.09; 95% confidence interval, 1.65 to 10.12; P=0.002). Incident advanced CKD was observed in 22 (47%) of those with baseline autonomic neuropathy and 46 (14%) of those without baseline autonomic neuropathy (P<0.001). Autonomic neuropathy was independently associated with incident advanced CKD (adjusted hazard ratio, 2.76; 95% confidence interval, 1.44 to 5.30; P=0.002).
  
  
  CONCLUSIONS
  Cardiac autonomic neuropathy was a strong independent predictor of the long-term risk of early progressive renal decline in type 1 diabetes. Future research should explore the mechanisms by which autonomic neuropathy may be associated with renal function loss.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Steven
authors.initials: S
authors.lastname: Orlov
authors.affiliation: Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada;
authors.forename: David Z I
authors.initials: DZ
authors.lastname: Cherney
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Health System, University of Michigan, Ann Arbor, Michigan; and.
authors.forename: Rodica
authors.initials: R
authors.lastname: Pop-Busui
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Leif E
authors.initials: LE
authors.lastname: Lovblom
authors.affiliation: Section on Genetics and Epidemiology, Research Division, Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Linda H
authors.initials: LH
authors.lastname: Ficociello
authors.affiliation: Section on Genetics and Epidemiology, Research Division, Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Smiles
authors.affiliation: Section on Genetics and Epidemiology, Research Division, Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: James H
authors.initials: JH
authors.lastname: Warram
authors.affiliation: Section on Genetics and Epidemiology, Research Division, Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Krolewski
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; bperkins@mtsinai.on.ca.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Perkins
mesh_terms: D000293:Adolescent; D000328:Adult; D001341:Autonomic Nervous System / Q000503:physiopathology*; D015415:Biomarkers / Q000097:blood; D001900:Boston / Q000453:epidemiology; D055316:Cystatin C / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000453:epidemiology*; D003928:Diabetic Nephropathies / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000175:diagnosis / Q000453:epidemiology* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006321:Heart / Q000294:innervation*; D006339:Heart Rate; D006801:Humans; D015994:Incidence; D007668:Kidney / Q000503:physiopathology*; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D016017:Odds Ratio; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D013997:Time Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; C525030:CST3 protein, human; D055316:Cystatin C
keywords: CKD; albuminuria; diabetes; renal function