Adenine crosses the biomarker bridge: from 'omics to treatment in diabetic kidney disease

Abstract

Enabling the early detection and prevention of diabetic kidney damage has potential to substantially reduce the global burden of kidney failure. There is a critical need for identification of mechanistic biomarkers that can predict progression and serve as therapeutic targets. In this issue of the JCI, Sharma and colleagues used an integrated multiomics approach to identify the metabolite adenine as a noninvasive biomarker of progression in early diabetic kidney disease (DKD). The highest tertile of urine adenine/creatinine ratio (UAdCR) was associated with higher risk for end-stage kidney disease and mortality across independent cohorts, including participants with early DKD without macroalbuminuria. Spatial metabolomics, single-cell transcriptomics, and experimental studies localized adenine to regions of tubular pathology and implicated the mTOR pathway in adenine-mediated tissue fibrosis. Inhibition of endogenous adenine production was protective in a diabetic model. These findings exemplify the potential for multiomics to uncover mechanistic biomarkers and targeted therapies in DKD.

Figure 1. Multiomics approaches enable discovery of mechanistic biomarkers and targeted therapies in diabetic kidney disease.

Kidney biopsy tissue and biospecimens (urine, plasma) are used to generate multiple types of molecular data, including single-cell transcriptomics, mass spectrometry imaging-based spatial metabolomics, and urine and plasma. These multimodal data are integrated using bioinformatic analysis to validate metabolites, cell types, and pathways. The pathways and biomarkers are then studied in experimental models to validate the target and allow for early-stage drug development. Finally, the novel biomarker is translated into mechanistic-based interventional clinical trials for clinical development of new DKD therapeutics. The UAdCR mechanistic biomarker could be used to stratify patients who are in the early stage of disease but at high risk for disease progression, to identify relevant subgroups of patients who are more likely to benefit from the targeted therapy for enrollment in clinical trials, and as a measure of target engagement in interventional trials of emerging therapeutics. DKD, diabetic kidney disease; HK-2, human kidney proximal tubular; MTAP, methylthioadenosine phosphorylase; MTC, murine kidney proximal tubular epithelial; mTOR, mammalian target of rapamycin; RNP, ribonucleoprotein; SGLT2i, sodium-glucose cotransporter-2 inhibitor; UAdCR, urine adenine/creatinine ratio.