Plasma Proteins Predict Kidney Function Trajectories in Type 2 Diabetes.

Abstract

Objective: The rate of decline in estimated glomerular filtration rate (eGFR) varies among patients with type 2 diabetes (T2D). We aimed to identify plasma proteins associated with diverse eGFR trajectories in T2D.

Methods: We performed latent class mixed models analysis among patients with T2D and relatively preserved kidney function (baseline eGFR ≥60 mL/min/1.73 m2) from the Singapore Study of Macro-angiopathy and Micro-Vascular Reactivity in Type 2 Diabetes (SMART2D) (n = 1285) and diabetic nephropathy (n = 798) cohorts to identify patterns of eGFR trajectories. Comprehensive proteomic association with eGFR trajectories was assessed using multivariable logistic regression in the SMART2D cohort.

Results: Three distinct eGFR trajectories groups-slow decline (92.2%), progressive decline (4.0%), and accelerated decline (3.8%)-were identified in SMART2D and validated in the diabetic nephropathy cohort. Participants in the accelerated decline group exhibited the highest risk of progression to end-stage kidney disease (log-rank test, P < .0001). Among 1448 proteins analyzed in the SMART2D cohort, 19 proteins, including KIM-1 (odds ratio [OR] = 2.95; 95% CI, 2.01-4.32; P = 2.95 × 10-8), MMP7 (OR = 16.5; 95% CI, 5.54-49.07; P = 4.61 × 10-7), and VSIG4 (OR = 7.38; 95% CI, 3.22-16.89; P = 2.24 × 10-6), were associated with accelerated decline and 1 protein (OR = 6.34; 95% CI, 2.77-14.52; P = 1.26 × 10-5) was associated with progressive decline, independent of traditional cardiorenal risk factors including baseline kidney function. Adding these proteins to clinical risk factors (age, sex, ethnicity, eGFR, urine albumin-to-creatinine ratio, HbA1c, diabetes duration, systolic blood pressure, triglyceride) improved area under the curve to 0.77 (delta 0.04, P = .057) for progressive decline and 0.93 (delta 0.09, P < .001) for accelerated decline.

Conclusion: Different plasma proteins are associated with progressive and accelerated eGFR decline, independent of traditional cardiorenal risk factors, some of which enhance eGFR trajectory prediction in patients with T2D.