title: The synergistic relationship between estimated GFR and microalbuminuria in predicting long-term progression to ESRD or death in patients with diabetes: results from the Kidney Early Evaluation Program (KEEP).
abstract: BACKGROUND
  Chronic kidney disease may complicate diabetes, often manifesting with reduced glomerular filtration rate (GFR), albuminuria, or both. Although greater albuminuria and lower estimated GFR both predict adverse prognosis, whether a synergistic prognostic interaction occurs in patients with diabetes has not been defined in a large national cohort study.
  
  
  METHODS
  We used 2000-2011 data from the National Kidney Foundation's Kidney Early Evaluation Program (KEEP) for 42,761 participants with diabetes. Kaplan-Meier survival analysis and multivariable Cox regression were used to ascertain the association of estimated GFR, albumin-creatinine ratio (ACR), and their interaction on all-cause mortality and progression to end-stage renal disease (ESRD) at a median 4 years of follow-up.
  
  
  RESULTS
  Of 42,761 participants with diabetes, 8,618 (20.2%) had estimated GFR <60 mL/min/1.73 m(2), 7,715 (18.0%) had ACR >30 mg/g, and 2,641 (6.2%) had both. The unadjusted incidence (per 1,000 person-years) of all-cause mortality increased from 3.1 (95% CI, 2.4-3.8) in participants with estimated GFR ≥ 105 mL/min/1.73 m(2) and no albuminuria to 73.7 (95% CI, 54.9-92.5) in participants with estimated GFR <30 mL/min/1.73 m(2) and macroalbuminuria (P < 0.001). Progression to ESRD likewise increased from 0.2 (95% CI, 0-0.4) to 220.4 (95% CI, 177.2-263.6) per 1,000 person-years (P < 0.001). After adjustment for confounders, both estimated GFR and albuminuria were associated independently with mortality and progression to ESRD, with a strong synergistic interaction (P for interaction < 0.001); estimated GFR <30 mL/min/1.73 m(2) and macroalbuminuria together were associated with a 5-fold higher risk of mortality and a more than 1,000-fold higher risk of progression to ESRD (compared with patients with estimated GFR >60 mL/min/1.73 m(2) and ACR <30 mg/g; P < 0.001 for both outcomes).
  
  
  CONCLUSIONS
  In this large cohort of diabetic KEEP participants with more than 170,000 person-years of follow-up, both estimated GFR and albuminuria were associated independently with mortality and progression to ESRD, with a strong synergistic interaction.
authors.affiliation: Washington University School of Medicine, Barnes Jewish Hospital, St Louis, MO, USA.
authors.forename: Amit P
authors.initials: AP
authors.lastname: Amin
authors.forename: Adam T
authors.initials: AT
authors.lastname: Whaley-Connell
authors.forename: Suying
authors.initials: S
authors.lastname: Li
authors.forename: Shu-Cheng
authors.initials: SC
authors.lastname: Chen
authors.forename: Peter A
authors.initials: PA
authors.lastname: McCullough
authors.forename: Mikhail N
authors.initials: MN
authors.lastname: Kosiborod
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000175:diagnosis / Q000453:epidemiology; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood*; D003928:Diabetic Nephropathies / Q000150:complications / Q000175:diagnosis / Q000453:epidemiology / Q000378:metabolism / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D016730:Program Development; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: D003404:Creatinine