Risk of ESRD and Mortality Associated With Change in Filtration Markers

Abstract

Background: Using change in estimated glomerular filtration rate (eGFR) based on creatinine concentration as a surrogate outcome in clinical trials of chronic kidney disease has been proposed. Risk for end-stage renal disease (ESRD) and all-cause mortality associated with change in concentrations of other filtration markers has not been studied in chronic kidney disease populations.

Study design: Observational analysis of 2 clinical trials.

Setting & participants: Participants in the MDRD (Modification of Diet in Renal Disease; n=317) Study and AASK (African American Study of Kidney Disease and Hypertension; n=373).

Predictors: Creatinine, cystatin C, β-trace protein (BTP), and β₂-microglobulin (B2M) were measured in serum samples collected at the 12- and 24-month follow-up visits, along with measured GFR (mGFR) at these time points.

Outcomes: ESRD and all-cause mortality.

Measurements: Poisson regression was used to estimate incidence rate ratios and 95% CIs for ESRD and all-cause mortality during long-term follow-up (10-16 years) per 30% decline in mGFR or eGFR for each filtration marker and the average of all 4 markers.

Results: 1-year decline in mGFR, eGFR_cr, eGFR_BTP, and the average of the 4 filtration markers was significantly associated with increased risk for incident ESRD in both studies (all P≤0.02). Compared to mGFR, only decline in eGFR_BTP was statistically significantly more strongly associated with ESRD risk in both studies (both P≤0.03). Decline in eGFR_cr, but not mGFR or the other filtration markers, was significantly associated with risk for all-cause mortality in AASK only (incidence rate ratio per 30% decline, 4.17; 95% CI, 1.78-9.74; P<0.001), but this association was not significantly different from decline in mGFR (P=0.2).

Limitations: Small sample size.

Conclusions: Declines in mGFR, eGFR_cr, eGFR_BTP, and the average of 4 filtration markers (creatinine, cystatin C, BTP, and B2M) were consistently associated with progression to ESRD.

Keywords: Beta-2-microglobulin (B2M); beta trace protein (BTP); creatinine; cystatin C; death; end-stage renal disease (ESRD); estimated GFR; filtration markers; glomerular filtration rate (GFR); incident ESRD; kidney function decline; measured GFR; mortality.

Figure 1

Flow Diagram of Study Participant Selection in the Modification of Diet in Renal Disease Study and the African American Study of Kidney Disease and Hypertension

Figure 2

Kernel Density Plot of Change in Measured and Estimated Glomerular Filtration Rate^a,b (A) in the Modification of Diet in Renal Disease Study and (B) in the African American Study of Kidney Disease and Hypertension ^amGFR in purple; eGFR_cr in orange; eGFR_cys in pink; eGFR_BTP in blue; eGFR_B2M in yellow; average of four filtration markers in black ^bMean (standard deviation) percent change over one year in the MDRD Study and AASK, respectively, was −10.0% (18.2%) and −4.2% (18.8%) for mGFR, −10.5% (19.0%) and −3.2% (16.9%) for eGFR_cr, −1.0% (17.5%) and −2.6% (16.1%) for eGFR_cys, −3.3% (11.6%) and −2.5% (22.5%) for eGFR_BTP, −6.6% (18.9%) and −3.8% (14.7%) for eGFR_B2M, and −5.4% (14.6%) and −3.0% (13.0%) for the average of the four filtration markers.

Figure 2

Kernel Density Plot of Change in Measured and Estimated Glomerular Filtration Rate^a,b (A) in the Modification of Diet in Renal Disease Study and (B) in the African American Study of Kidney Disease and Hypertension ^amGFR in purple; eGFR_cr in orange; eGFR_cys in pink; eGFR_BTP in blue; eGFR_B2M in yellow; average of four filtration markers in black ^bMean (standard deviation) percent change over one year in the MDRD Study and AASK, respectively, was −10.0% (18.2%) and −4.2% (18.8%) for mGFR, −10.5% (19.0%) and −3.2% (16.9%) for eGFR_cr, −1.0% (17.5%) and −2.6% (16.1%) for eGFR_cys, −3.3% (11.6%) and −2.5% (22.5%) for eGFR_BTP, −6.6% (18.9%) and −3.8% (14.7%) for eGFR_B2M, and −5.4% (14.6%) and −3.0% (13.0%) for the average of the four filtration markers.

Figure 3

Adjusted^a Risk of Incident End-Stage Renal Disease According to Change^b in Measured and Estimated Glomerular Filtration Rate^c (A) in the Modification of Diet in Renal Disease Study and (B) in the African American Study of Kidney Disease and Hypertension ^aAdjusted for age, sex, race, body mass index, systolic blood pressure, diabetes, total cholesterol, randomized treatment group, study group (for MDRD Study only), and first measurement of mGFR or eGFR for the respective marker ^bPercent change modeled as linear spline terms with one knot at 0% ^cmGFR in purple; eGFR_cr in orange; eGFR_cys in pink; eGFR_BTP in blue; eGFR_B2M in yellow; average of four filtration markers in black

Figure 3

Adjusted^a Risk of Incident End-Stage Renal Disease According to Change^b in Measured and Estimated Glomerular Filtration Rate^c (A) in the Modification of Diet in Renal Disease Study and (B) in the African American Study of Kidney Disease and Hypertension ^aAdjusted for age, sex, race, body mass index, systolic blood pressure, diabetes, total cholesterol, randomized treatment group, study group (for MDRD Study only), and first measurement of mGFR or eGFR for the respective marker ^bPercent change modeled as linear spline terms with one knot at 0% ^cmGFR in purple; eGFR_cr in orange; eGFR_cys in pink; eGFR_BTP in blue; eGFR_B2M in yellow; average of four filtration markers in black

Figure 4

Adjusted^a Risk of All-Cause Mortality According to Change^b in Measured and Estimated Glomerular Filtration Rate^c (A) in the Modification of Diet in Renal Disease Study and (B) in the African American Study of Kidney Disease and Hypertension ^aAdjusted for age, sex, race, body mass index, systolic blood pressure, diabetes, total cholesterol, randomized treatment group, study group (for MDRD Study only), and first measurement of mGFR or eGFR for the respective marker ^bPercent change modeled as linear spline terms with one knot at 0% ^cmGFR in purple; eGFR_cr in orange; eGFR_cys in pink; eGFR_BTP in blue; eGFR_B2M in yellow; average of four filtration markers in black

Figure 4

Adjusted^a Risk of All-Cause Mortality According to Change^b in Measured and Estimated Glomerular Filtration Rate^c (A) in the Modification of Diet in Renal Disease Study and (B) in the African American Study of Kidney Disease and Hypertension ^aAdjusted for age, sex, race, body mass index, systolic blood pressure, diabetes, total cholesterol, randomized treatment group, study group (for MDRD Study only), and first measurement of mGFR or eGFR for the respective marker ^bPercent change modeled as linear spline terms with one knot at 0% ^cmGFR in purple; eGFR_cr in orange; eGFR_cys in pink; eGFR_BTP in blue; eGFR_B2M in yellow; average of four filtration markers in black