Urinary A- and C-megalin predict progression of diabetic kidney disease: a retrospective cohort study

Background Urinary excretion of megalin, a proximal tubular endocytic receptor, may be associated with the development and progression of diabetic kidney disease (DKD). However, no studies have assessed whether the levels of the urinary ectodomain (A-megalin) and full-length (C-megalin) forms of megalin can predict DKD progression. Methods We evaluated the correlation of urinary A-megalin levels of 34 patients with type 2 diabetes as measured by novel reducing and previous methods. Then, we retrospectively analyzed 188 type 2 diabetes patients not taking sodium glucose cotransporter 2 (SGLT2) inhibitors in order to investigate whether urinary A- and C-megalin might be used as predictors of kidney outcomes. The median observation period was 3.96 years. The associations between the baseline urinary A-megalin measured by the novel method and/or C-megalin levels and the subsequent estimated glomerular filtration rate (eGFR) slope were analyzed using a generalized estimating equation. Patients were categorized into higher or lower groups based on the optimal cutoff values, obtained from a receiver operating characteristic (ROC) curve, of the two forms of urinary megalin. Results Urinary A-megalin levels measured by the two methods were strongly correlated. The eGFR slopes of the higher A-megalin and C-megalin groups were −0.904 (95% confidence interval [CI] −1.584, −0.224) and −0.749 (95% CI −1.312, −0.186) ml/min/1.73 m2 per year steeper than those of the lower groups, respectively. Moreover, the eGFR slope was −1.888 (95% CI −2.764, −1.011) ml/min/1.73 m2 per year steeper in the group with both higher A- and higher C-megalin than in the other groups. These results remained significant when adjusted for albuminuria or known tubular injury markers. Conclusions Our novel method allows urinary A-megalin measurements to be performed more easily. Baseline urinary megalin levels were associated with the subsequent eGFR slope independently of known biomarkers in type 2 diabetes patients not receiving SGLT2 inhibitors. These two forms of megalin may be distinct urinary biomarkers of the progression of DKD.