Oxidized LDL Modifies the Association between Proteinuria and Deterioration of Kidney Function in Proteinuric Diabetic Kidney Disease

Proteinuria is characterized by low accuracy for predicting onset and development of diabetic kidney disease (DKD) because it is not directly associated with molecular changes that promote DKD, but is a result of kidney damage. Oxidized low-density lipoprotein (ox-LDL) reflects oxidative stress and endothelial dysfunction, both underlying the development of proteinuria and loss of kidney function in DKD. We aimed to investigate whether ox-LDL modifies the association between proteinuria and progression of DKD in a cohort of 91 patients with proteinuric DKD and diabetic retinopathy, followed for 10 years. The primary endpoint was a combined kidney outcome of eGFR decline ≥30% or progression to end-stage kidney disease. After the end of the study, we considered the percentage change of eGFR over time as our secondary outcome. Proteinuria was associated with both outcomes, and ox-LDL amplified the magnitude of this link (p < 0.0001 for primary and p < 0.0001 for secondary outcome, respectively). After adjustment for duration of diabetes, history of cardiovascular disease and serum albumin, ox-LDL remained a significant effect modifier of the association between proteinuria and eGFR decline over time (p = 0.04). Our study shows that in proteinuric DKD, circulating ox-LDL levels amplified the magnitude of the association between proteinuria and progression of DKD.