Morphometric-molecular Approaches to Human Diabetic Kidney Disease and Chronic Kidney Disease*
Jeff Hodgin, MD
Assistant Professor of Pathology, University of St. Andrews
The kidney biopsy is an essential component for the diagnosis and effective therapeutic management of patients with kidney disease, however most analyses are qualitative and necessarily descriptive, lacking quantitative measurements and evaluation of underlying molecular mechanisms. Patients with diabetes have a significant risk of developing diabetic kidney disease (DKD) that often progresses to end-stage renal disease (ESRD) and imparts excess cardiovascular morbidity and mortality.
Importantly, structural changes of the renal tissue precede the clinical features used to diagnose DKD, however, the molecular networks that lead to changes in kidney architecture and subsequent functional impairment have not been well characterized. We have analyzed detailed morphometric and molecular data obtained from protocol kidney biopsies from study participants with type 2 diabetes mellitus, and normo- or microalbuminuria, as part of the “Renoprotection in Early Diabetic Nephropathy in Pima Indians” study.
By integrating fractional interstitial area (FIA) with whole-genome intra-renal transcripts analysis, we have identified candidate molecular mechanisms activated in early DKD. The gene sets linked to early structural damage and long-term outcomes represent starting points for the identification of non-invasive biomarkers of renal fibrosis and progression of DKD. Most importantly, they suggest that the continuous activation of a subset of molecular pathways throughout the DKD trajectory represent potential therapeutic targets. We are expanding this work by integrating additional morphometric features in DKD and other types of chronic kidney disease with molecular (transcriptomic) signatures and clinical outcomes with the eventual goal of automated analyses suitable for the clinical setting.