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

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.

Figure 1

Probability of mortality and progression to end-stage renal disease (ESRD). LOWESS is a curve-fitting tech nique that provides locally weighted scatterplot smoothing. These graphs are produced by the following methodology: for each participant who lived or died (y_i), a corresponding smoothed value of estimated glomerular filtration rate (eGFR; x_i) was generated. The smoothed values of eGFR were obtained by running a regression of the dependent variable (mortality; y_i) on the independent variable (eGFR; x_i) and a few data near this point. The regression was weighted so the central point (x_i; y_i) was given the highest weight, and points farther away (based on the absolute distance |x_j – x_ij|), less weight. The estimated regression line then was used to predict the smoothed value of eGFR. Because a separate weighted regression was performed for every point in the data, the procedure was repeated thou sands of times (exactly 42,761 times) to obtain the remaining smoothed values and the curves. Abbreviation: ACR, albumin-creatinine ratio.

Figure 2

Kaplan-Meier estimates of long-term survival by (A) estimated glomerular rate (eGFR; mL/min/1.73 m²) and (B) albumin-creatinine ratio (ACR; mg/g). Abbreviation: ESRD, end-stage renal disease.

Figure 3

Kaplan-Meier estimates of long-term end-stage renal disease (ESRD) free probability by (A) estimated glomerular rate (eGFR; mL/min/1.73 m²) and (B) albumin-creatinine ratio (ACR; mg/g).