Plasma Biomarkers and Kidney Function Decline in Early and Established Diabetic Kidney Disease

Abstract

Biomarkers of diverse pathophysiologic mechanisms may improve risk stratification for incident or progressive diabetic kidney disease (DKD) in persons with type 2 diabetes. To evaluate such biomarkers, we performed a nested case-control study (n=190 cases of incident DKD and 190 matched controls) and a prospective cohort study (n=1156) using banked baseline plasma samples from participants of randomized, controlled trials of early (ACCORD) and advanced (VA NEPHRON-D) DKD. We assessed the association and discrimination obtained with baseline levels of plasma TNF receptor-1 (TNFR-1), TNFR-2, and kidney injury molecule-1 (KIM-1) for the outcomes of incident DKD (ACCORD) and progressive DKD (VA-NEPHRON-D). At baseline, median concentrations of TNFR-1, TNFR-2, and KIM-1 were roughly two-fold higher in the advanced DKD population (NEPHRON-D) than in the early DKD population (ACCORD). In both cohorts, patients who reached the renal outcome had higher baseline levels than those who did not reach the outcome. Associations between doubling in TNFR-1, TNFR-2, and KIM-1 levels and risk of the renal outcomes were significant for both cohorts. Inclusion of these biomarkers in clinical models increased the area under the curve (SEM) for predicting the renal outcome from 0.68 (0.02) to 0.75 (0.02) in NEPHRON-D. Systematic review of the literature illustrated high consistency in the association between these biomarkers of inflammation and renal outcomes in DKD. In conclusion, TNFR-1, TNFR-2, and KIM-1 independently associated with higher risk of eGFR decline in persons with early or advanced DKD. Moreover, addition of these biomarkers to clinical prognostic models significantly improved discrimination for the renal outcome.

Figure 1.

Adjusted OR for the renal outcome per doubling in plasma biomarkers in ACCORD and VA-NEPHRON-D. After adjustment for all covariates, including baseline eGFR and UACR, TNFR1, TNFR2, and KIM-1 were significantly associated with the renal end point. All ORs are adjusted for treatment arm, baseline eGFR, albuminuria, age, race, systolic and diastolic BP, and medications (fibrates/ ACEis/ARBs). In ACCORD, renal end point is defined as achieving an eGFR<60 ml/min per 1.73 m² along with a sustained (on two or more visits ≥3 months apart) decline in eGFR of ≥40% from baseline eGFR. In VA-NEPHRON-D, renal outcome is defined as the occurrence of a decline in the eGFR (an absolute decrease of ≥30 ml/min per 1.73 m² if the eGFR was ≥60 ml/min per 1.73 m² at randomization or a relative decrease of ≥50% if the eGFR was <60 ml/min per 1.73 m²) or ESRD (defined by the initiation of maintenance dialysis, receipt of kidney transplant, or an eGFR of <15 ml/min per 1.73 m²).