Project Summary/Abstract
This project will build a new kidney biopsy cohort to characterize the molecular, morphometric, and metabolic
features of diabetic kidney disease (DKD) over the modern clinical course of type 1 diabetes (T1D). Landmark
kidney biopsy studies have enhanced our understanding of DKD pathogenesis. However, advances in
continuous glucose monitoring and automated insulin delivery have changed diabetes management and the
clinical course of DKD in T1D. Moreover, innovation in molecular methods to interrogate kidney tissue, such as
single-cell RNA sequencing (scRNA-seq), allows characterization of DKD at a resolution not previously
possible. Based on published work and our preliminary data, we hypothesize that perturbed kidney energetics
and hypoxia are central metabolic pathways in the development of DKD in T1D. We will test this hypothesis by
creating a unique new longitudinal kidney biopsy cohort (N=100) spanning the critical duration of T1D over
which DKD initiates and progresses (5-30 years) and leveraging our existing vanguard biopsy cohort (N=30).
Normative kidney biopsy data will be provided from our existing cohort of healthy controls (N=20), the Kidney
Precision Medicine Project (KPMP), and additional living kidney donor biopsies. We will implement state-of-
the-art molecular (scRNA-seq) and morphometric interrogation of kidney tissue and rigorous metabolic
phenotyping. Specifically, we aim to: (1) define differences in kidney energetics and hypoxia over the course of
T1D; (2) test associations of the transcriptomic signatures of hypoxia with the structural lesions and clinical
manifestations of progressive DKD; and (3) explore the mechanistic correlates of perturbed kidney energetics
and hypoxia within a subset of participants with T1D with repeat kidney biopsies. This work will help define the
role of perturbed energetics and hypoxia in DKD as well as risk factors for and consequences of kidney
hypoxia in T1D. This study will also generate a valuable repository of data, biosamples, and kidney tissue for
further analysis of DKD in T1D, made publicly available through the KPMP platform.