title: Kidney injury molecule-1 and the loss of kidney function in diabetic nephropathy: a likely causal link in patients with type 1 diabetes.
abstract: OBJECTIVE
  We evaluated the predictive value and clinical benefit of urinary kidney injury molecule (KIM)-1 for progression of diabetic nephropathy (DN) in type 1 diabetes. We also investigated its causal role for the decrease of estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) approach.
  
  
  METHODS
  We followed 1,573 patients with type 1 diabetes for 6 years. KIM-1 was measured at baseline and normalized with urinary creatinine. KIM-1 predictive value was evaluated by Cox regression, while its added predictive benefit was evaluated using a panel of statistical indexes. The causality for the loss of renal function was evaluated with MR, utilizing the top signal from our genome-wide association study (GWAS) as the instrumental variable.
  
  
  RESULTS
  KIM-1 was not an independent predictor of progression of DN when adjusted for albumin excretion rate (AER) and added no prognostic benefit to AER or eGFR. In multiple regressions, KIM-1 was associated with lower eGFR independently of diabetes duration (β = -4.066; P < 0.0001) but not of AER. In our GWAS, rs2036402 in the KIM1 gene was strongly associated with KIM-1 (β = -0.51; P = 6.5 × 10(-38)). In the MR, KIM-1 was associated with lower eGFR, independently of diabetes duration and AER (β = -5.044; P = 0.040), suggesting a causal relationship.
  
  
  CONCLUSIONS
  KIM-1 did not predict progression to end-stage renal disease independently of AER and added no prognostic benefit to current biomarkers. Nevertheless, the MR showed that the inverse association of increased KIM-1 levels with lower eGFR is likely to represent a causal link.
authors.affiliation: 2nd Clinical Department, Diabetes Nutrition and Metabolic Diseases Chair, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Nicolae M
authors.initials: NM
authors.lastname: Panduru
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Sandholm
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Saraheimo
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Emma H
authors.initials: EH
authors.lastname: Dahlström
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Lena M
authors.initials: LM
authors.lastname: Thorn
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gordin
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Nina
authors.initials: N
authors.lastname: Tolonen
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Johan
authors.initials: J
authors.lastname: Wadén
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Valma
authors.initials: V
authors.lastname: Harjutsalo
authors.affiliation: Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.affiliation: Stoffwechselzentrum Rhein Pfalz, Mannheim, Germany.
authors.forename: Per M
authors.initials: PM
authors.lastname: Humpert
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia per-henrik.groop@helsinki.fi.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
mesh_terms: D000328:Adult; D017668:Age of Onset; D015415:Biomarkers / Q000652:urine; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D055106:Genome-Wide Association Study; D005919:Glomerular Filtration Rate / Q000235:genetics; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007676:Kidney Failure, Chronic / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000652:urine*; D015999:Multivariate Analysis; D011379:Prognosis; D011991:Receptors, Virus / Q000235:genetics
chemical_list: D015415:Biomarkers; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D011991:Receptors, Virus