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)

Am J Kidney Dis. 2013 Apr;61(4 Suppl 2):S12-23. doi: 10.1053/j.ajkd.2013.01.005.


Introduction: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Albuminuria* / diagnosis
  • Albuminuria* / epidemiology
  • Cohort Studies
  • Creatinine / blood*
  • Diabetic Nephropathies* / complications
  • Diabetic Nephropathies* / diagnosis
  • Diabetic Nephropathies* / epidemiology
  • Diabetic Nephropathies* / metabolism
  • Diabetic Nephropathies* / physiopathology
  • Disease Progression
  • Female
  • Glomerular Filtration Rate*
  • Humans
  • Kaplan-Meier Estimate
  • Kidney Failure, Chronic* / epidemiology
  • Kidney Failure, Chronic* / etiology
  • Kidney Failure, Chronic* / prevention & control
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • Program Development
  • Proportional Hazards Models
  • Risk Assessment
  • Risk Factors
  • United States / epidemiology


  • Creatinine