Spatial metabolomics for human kidney interrogation of early diabetic kidney disease

Kidney hypoxia, stemming from a mismatch between increased renal energy demand and impaired substrate metabolism, is emerging as a unifying early pathway in the development of diabetic kidney disease (DKD) and a potential therapeutic target. In our JDRF-funded CROCODILE study we are quantifying kidney O2 consumption by 11C-acetate PET, kidney oxygenation by blood oxygen level dependent MRI, glomerular filtration rate and renal plasma flow by iohexol and p-aminohippurate clearances, morphometric and transcriptomic analyses of kidney tissue from research biopsies, insulin sensitivity by hyperinsulinemic-euglycemic clamp and mitochondrial function by plasma and urine metabolomics in young adults with and without type 1 diabetes (T1D). However, plasma and urine metabolomics are not kidney-specific and identified compounds may not be representative of the intrarenal milieu. Accordingly, metabolic phenotyping of the kidney tissue to interrogate tissue-specific metabolic perturbations of early DKD in T1D would enhance our study design. The DRC P&F Grant would provide support to add spatial metabolomics analyses of kidney tissues by matrix-assisted laser desorption/ ionization mass spectrometry imaging from young adults with (n=20) and without (n=20) T1D. Our central objective is to quantify metabolite data in discrete kidney compartments in order to define the metabolic pathways that may drive early DKD in T1D.