suPAR Is Associated with Progressive Albuminuria in Type 1 Diabetes

BACKGROUND AND OBJECTIVES: Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived glycoprotein implicated in chronic kidney disease (CKD) and glomerulopathy. suPAR predicts CKD progression, but whether it is associated with longitudinal albuminuria worsening, including in patients without established albuminuria, is untested in diabetic kidney disease (DKD). We examined this in type 1 diabetes using albumin excretion rate (AER) trajectory. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: Post hoc analysis of 506 participants with a single baseline suPAR measurement from the PERL trial, a 3-year multicenter randomized controlled trial in type 1 diabetes with early-to-moderate DKD. Linear mixed models estimated suPAR's association with AER and iohexol-measured glomerular filtration rate (iGFR) trajectories. Structural equation modeling assessed whether albuminuria level accounted for the association between suPAR and iGFR decline. RESULTS: Mean age was 51 years, 34% female, diabetes duration 35 years, iGFR 68 mL/min/1.73 m2, median AER 44 μg/min, and median suPAR 3.43 ng/mL. Each suPAR doubling was associated with 11.6% per year additional AER increase (P<0.001), with a dose-response across quartiles and robust to sensitivity analyses. Time-lagged analysis confirmed the association with subsequent AER worsening (P=0.004). Among 125 eGFR-decline qualifiers (predominantly normoalbuminuric), higher suPAR was associated with accelerated AER worsening (+13.1%/yr per doubling, P=0.005; +11.7%/yr in the 101 normoalbuminuric), although none crossed the proteinuria threshold. suPAR was also associated with AER category progression (HR 1.61, P=0.002) and ≥40% eGFR loss (HR 1.86, P=0.01). suPAR was not independently associated with GFR slope (total effect P=0.49); its association with lower GFR was accounted for by albuminuria level (indirect effect -0.59 mL/min/yr per doubling, P<0.001). CONCLUSIONS: suPAR was independently associated with progressive albuminuria worsening in type 1 diabetes with DKD, including accelerated worsening among normoalbuminuric patients. These associations are consistent with suPAR marking active podocyte injury and support its evaluation for early risk stratification.