Alternative kidney filtration markers and the risk of major macrovascular and microvascular events, and all-cause mortality in individuals with type 2 diabetes in the ADVANCE trial

Background: Creatinine-based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be useful in adults with diabetes, but few studies examined the associations with risk of clinical outcomes. Methods: In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, we evaluated whether baseline levels and change in eGFR based on creatinine (Cr), cystatin c (Cys), β₂-microglobulin (B2M), eGFR_Cr-Cys, and the average of three estimates (eGFR_Cr-Cys-B2M) assessed in 7217 participants at baseline and a random sample of 640 participants at the 1-year visit are associated with clinical outcomes. We examined associations with major macrovascular and microvascular events together and separately and all-cause mortality using Cox regression models, adjusting for established risk factors. Results: Over a median follow-up of 5 years, 1313 major macrovascular (n = 748) and microvascular events (n = 637), and 743 deaths occurred. Lower levels of eGFR based on all filtration markers individually and combined were associated with 1.4 to 3.0 times higher risk of major macrovascular and microvascular events (combined and separately) and all-cause mortality. Per 30% decline in eGFR_Cys, eGFR _Cr-Cys, and eGFR_Cr-Cys-B2M were associated with a >2-fold higher risk of all clinical outcomes. Conclusions: In adults with type 2 diabetes, baseline levels of eGFR based on alternative filtration markers and per 30% decline in eGFR_Cys, eGFR _Cr-Cys, and eGFR_Cr-Cys-B2M were associated with clinical outcomes. Measurement of alternative filtration markers, particularly B2M in adults with type 2 diabetes may be warranted.