title: Evidence for two distinct phenotypes of chronic kidney disease in individuals with type 1 diabetes mellitus.
abstract: In a retrospective, observational, cross-sectional, single-centre study, we assessed the prevalence and correlates of different CKD phenotypes (with and without albuminuria) in a large cohort of patients of white ethnicity with type 1 diabetes.
  
  
  
  From 2001 to 2009, 408 men and 369 women with type 1 diabetes (age 40.2 ± 11.7 years, diabetes duration 19.4 ± 12.2 years, HbA1c7.83 ± 1.17% [62.0 ± 12.9 mmol/mol]) were recruited consecutively. Albumin-to-creatinine ratio (ACR) and eGFR (Modification of Diet in Renal Disease) were obtained for all individuals, together with CKD stage. Diabetic retinopathy and peripheral polyneuropathy were detected in 41.5% and 8.1%, respectively, and cardiovascular disease (CVD) occurred in 8.5%. Adjudications of CKD phenotype were made by blinded investigators.
  
  
  
  Normo- (ACR <3.4), micro- (ACR 3.4-34) or macroalbuminuria (ACR ≥34 mg/mmol) were present in 91.6%, 6.4% and 1.9% of individuals, respectively. eGFR categories 1 (≥90 ml min-1[1.73 m]-2), 2 (60-89 ml min-1[1.73 m]-2) and 3 (<60 ml min-1[1.73 m]-2) were present in 57.3%, 39.0% and 3.7%, respectively. The majority of participants had no CKD (89.4%), while stages 1-2 and ≥3 CKD were detected in 6.8% and 3.7%, respectively. The albuminuric (Alb+) and non-albuminuric (Alb-) phenotypes were present in 12 (41.4%) and 17 (58.6%) individuals with stage ≥3 CKD, respectively. Individuals with an ACR <3.4 mg/mmol were subdivided into those with normal albuminuria (<1.1 mg/mmol; 77.2%) and mildly increased albuminuria (1.1-3.4 mg/mmol; 14.4%), and individuals with stage 2 CKD were subdivided into those with eGFR 75-89 ml min-1[1.73 m]-2and 60-74 ml min-1[1.73 m]-2. ACR <3.4 mg/mmol (88.7%) and even <1.1 mg/mmol (70.4%) were common in individuals with eGFR 60-74 ml min-1[1.73 m]-2. The prevalence of ACR <1.1 mg/mmol was lower but still significant (34.5%) in those with stage ≥3 CKD. In logistic regression analysis, stages 1-2 and ≥3 CKD were independently associated with age, HbA1c, γ-glutamyltransferase, fibrinogen, hypertension, but not with sex, BMI, smoking, HDL-cholesterol or triacylglycerol. Inclusion of advanced retinopathy removed HbA1cfrom the model. The CKD Alb+phenotype correlated with diabetes duration, HbA1c, HDL-cholesterol, fibrinogen and hypertension, while the CKD Alb-phenotype was associated with age and hypertension, but not with diabetes duration, HbA1cand fibrinogen.
  
  
  
  The Alb-CKD phenotype is present in a significant proportion of individuals with type 1 diabetes supporting the hypothesis of two distinct pathways (Alb+and Alb-) of progression towards advanced kidney disease in type 1 diabetes. These are probably distinct pathways as suggested by different sets of covariates associated with the two CKD phenotypes.
authors.affiliation: Diabetes and Metabolic Disease Section, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, 2 Via Paradisa, 56124, Pisa, Italy. pgiuse@immr.med.unipi.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Penno
authors.affiliation: Diabetes and Metabolic Disease Section, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, 2 Via Paradisa, 56124, Pisa, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Russo
authors.affiliation: Diabetes and Metabolic Disease Section, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, 2 Via Paradisa, 56124, Pisa, Italy.
authors.forename: Monia
authors.initials: M
authors.lastname: Garofolo
authors.affiliation: Diabetes and Metabolic Disease Section, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, 2 Via Paradisa, 56124, Pisa, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Daniele
authors.affiliation: Diabetes and Metabolic Disease Section, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, 2 Via Paradisa, 56124, Pisa, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Lucchesi
authors.affiliation: Diabetes and Metabolic Disease Section, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, 2 Via Paradisa, 56124, Pisa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Giusti
authors.affiliation: Diabetes and Metabolic Disease Section, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, 2 Via Paradisa, 56124, Pisa, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Sancho Bornez
authors.affiliation: Diabetes and Metabolic Disease Section, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, 2 Via Paradisa, 56124, Pisa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bianchi
authors.affiliation: Diabetes and Metabolic Disease Section, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, 2 Via Paradisa, 56124, Pisa, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Dardano
authors.affiliation: Diabetes and Metabolic Disease Section, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, 2 Via Paradisa, 56124, Pisa, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Miccoli
authors.affiliation: Diabetes and Metabolic Disease Section, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, 2 Via Paradisa, 56124, Pisa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Del Prato
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000473:pathology / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000473:pathology / Q000503:physiopathology; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D051436:Renal Insufficiency, Chronic / Q000473:pathology* / Q000503:physiopathology; D012189:Retrospective Studies; D012307:Risk Factors
keywords: Albuminuria; Chronic kidney disease; Diabetic retinopathy; Glomerular filtration rate; Type 1 diabetes mellitus