Glomerular Structure and Function in Type 2 Diabetes Stratified by Glomerular Basement Membrane Thickening

Introduction: Glomerular structural-functional relationships in diabetes were tested, stratifying by glomerular basement membrane (GBM) thickness, an approach not previously explored. Methods: Research kidney biopsies were performed in 30 people with type 2 diabetes and any of the following baseline characteristics: moderate/severe albuminuria (UACR >30µg/mg), low eGFR (45-60mL/min/1.73m2, with and without albuminuria), or severe/proliferative retinopathy. Stereologic analyses were performed, and participants were stratified by the presence of GBM thickening. Standard light microscopy (LM) for glomerular, vascular and tubulointerstitial lesions were performed in a subset (N=19) with available paraffin embedded tissue. Creatinine values were collected and eGFR slope calculated. Results: Thickening of the GBM was present in 21 of 30 participants. Clinically, the GBM thickened group differed numerically from the normal GBM group only in having a higher HbA1c (7.9% versus 6.6%) and greater prevalence of albuminuria (67% versus 22%). Correlations with eGFR slope were not present in the full cohort, but were present in the group with GBM thickening: fractional volume of mesangium per glomerulus (R=-0.4; p=0.03), fractional volume of mesangial matrix per glomerulus (R=-0.5; p=0.04), and podocyte foot process width (R=-0.5; p=0.03). Results were unchanged after excluding two participants with normal UACR and eGFR. In the 6 members of the subgroup without GBM thickening who had available LM, two had hypertensive nephrosclerosis, three had significant vascular lesions but no interstitial fibrosis and one had mild vascular and interstitial lesions. Conclusion: This study highlights the need for further work to better categorize renal structural phenotypes in patients with T2D to facilitate kidney disease prognostication, novel biomolecular target discovery and therapies, and renal structural endpoints for clinical trials.