Heterogeneity in the relationships between albuminuria and glomerular structure in type 1 and type 2 diabetes

Introduction: Kidney structural-functional relationship studies have been critical in understanding diabetic kidney disease (DKD) evolution. However, most such studies were performed in persons with type 1 diabetes, where diabetic glomerular lesions are strongly associated with albumin excretion rate (AER). Here, we compare DKD structural-functional relationships in type 1 and type 2 diabetes. Methods: To better understand the evolution of DKD in type 2 diabetes, analyses of glomerular structure/albuminuria relationships were performed in 133 research volunteers with type 2 and 161 with type 1 diabetes matched for AER compared to 95 living donor kidney biopsies as controls. Results: Morphometric measures of DKD glomerular lesions were more advanced and showed stronger relationships with AER in persons with type 1 vs type 2 diabetes. K-means cluster analysis based on distance from a structural-functional relationship model derived from data of research participants with type 1 diabetes yielded two clusters: 74% of participants with type 2 diabetes were in Cluster 1, which also included most participants with type 1 diabetes, while 26% of participants with type 2 diabetes (39% of type 2 cases with increased AER) were in Cluster 2 and showed greater AER than predicted by their DKD glomerular lesions based on the model. Among those with type 2 diabetes, despite excessive AER in Cluster 2, DKD glomerular lesions and podocyte structural parameters were similar between the two clusters. However, adjusted for AER, individuals with type 2 diabetes in Cluster 1 had more severe DKD lesions and approximately four-fold greater rates of glomerular filtration rate decline over nine to ten years follow up than those in Cluster 2. Conclusions: Kidney structural-functional relationships are heterogeneous in individuals with type 2 diabetes, and this heterogeneity is linked to glomerular filtration rate loss over time. Our investigation calls for further studies to better understand factors involved in this heterogeneity.