J Clin Invest. 2023 Oct 16;133(20):e174015. doi: 10.1172/JCI174015.
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.
早期发现和预防糖尿病肾病有可能显著降低全球肾衰竭负担。目前迫切需要确定能够预测疾病进展并作为治疗靶点的机制生物标志物。在本期《临床研究杂志》中，Sharma 及其同事采用整合的多组学方法，发现代谢物腺嘌呤可作为早期糖尿病肾病（DKD）进展的无创生物标志物。尿液腺嘌呤/肌酐比值（UAdCR）最高三分位与终末期肾病和死亡率风险增加相关，在包括无大量白蛋白尿的早期 DKD 患者在内的多个独立队列中均观察到了这一结果。空间代谢组学、单细胞转录组学和实验研究将腺嘌呤定位到肾小管病变区域，并提示 mTOR 通路参与了腺嘌呤介导的组织纤维化。内源性腺嘌呤生成的抑制在糖尿病模型中具有保护作用。这些发现体现了多组学在揭示 DKD 机制生物标志物和靶向治疗方面的潜力。
