title: Synergism between circulating tumor necrosis factor receptor 2 and HbA(1c) in determining renal decline during 5-18 years of follow-up in patients with type 1 diabetes and proteinuria.
abstract: OBJECTIVE
  We studied the serum concentration of tumor necrosis factor receptor 2 (TNFR2) and the rate of renal decline, a measure of the intensity of the disease process leading to end-stage renal disease (ESRD).
  
  
  METHODS
  A cohort of 349 type 1 diabetic patients with proteinuria was followed for 5-18 years. Serum TNFR2, glycated hemoglobin A1c (HbA1c), and other characteristics were measured at enrollment. We used a novel analytic approach, a joint longitudinal-survival model, fitted to serial estimates of glomerular filtration rate (eGFR) based on serum creatinine (median seven per patient) and time to onset of ESRD (112 patients) to estimate the rate of renal decline (eGFR loss).
  
  
  RESULTS
  At enrollment, all patients had chronic kidney disease stage 1-3. The mean (±SD) rate of eGFR loss during 5-18 years of follow-up was -5.2 (±4.9) mL/min/1.73 m(2)/year. Serum TNFR2 was the strongest determinant of renal decline and ESRD risk (C-index 0.79). The rate of eGFR loss became steeper with rising concentration of TNFR2, and elevated HbA1c augmented the strength of this association (P = 0.030 for interaction). In patients with HbA1c ≥10.1% (87 mmol/mol), the difference in the rate of eGFR loss between the first and fourth quartiles of TNFR2 was 5.4 mL/min/1.73 m(2)/year, whereas it was only 1.9 in those with HbA1c <7.9% (63 mmol/mol).
  
  
  CONCLUSIONS
  Circulating TNFR2 is a major determinant of renal decline in patients with type 1 diabetes and proteinuria. Elevated HbA1c magnifies its effect. Although the mechanisms of this synergism are unknown, our findings allow us to stratify patients according to risk of ESRD.
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Skupien
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: James H
authors.initials: JH
authors.lastname: Warram
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Monika A
authors.initials: MA
authors.lastname: Niewczas
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Gohda
authors.affiliation: Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Malecki
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
authors.forename: Josyf C
authors.initials: JC
authors.lastname: Mychaleckyj
authors.affiliation: Department of Biostatistics and Division of Geriatric Medicine, University of Michigan Health System, Ann Arbor, MI.
authors.forename: Andrzej T
authors.initials: AT
authors.lastname: Galecki
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA andrzej.krolewski@joslin.harvard.edu.
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Krolewski
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000503:physiopathology; D004357:Drug Synergism; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006442:Glycated Hemoglobin / Q000032:analysis*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000175:diagnosis* / Q000209:etiology; D007677:Kidney Function Tests; D008137:Longitudinal Studies; D008297:Male; D011379:Prognosis; D011507:Proteinuria / Q000150:complications* / Q000503:physiopathology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood*; D013997:Time Factors
chemical_list: D015415:Biomarkers; D006442:Glycated Hemoglobin; D047889:Receptors, Tumor Necrosis Factor, Type II; C415902:TNFRSF1B protein, human; C517652:hemoglobin A1c protein, human