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Role of endogenous adenine in kidney failure and mortality with diabetes.

Kumar SharmaGuanshi ZhangJens HansenPetter BjornstadHak Joo LeeRajasree MenonLeila HejaziJian-Jun LiuAnthony FranzoneHelen C LookerByeong Yeob ChoiRoman FernandezManjeri A VenkatachalamLuxcia KugathasanVikas S SridharLoki NatarajanJing ZhangVarun SharmaBrian KwanSushrut WaikarJonathan HimmelfarbKatherine TuttleBryan KestenbaumTobias FuhrerHarold FeldmanIan H de BoerFabio C TucciJohn SedorHiddo Lambers HeerspinkJennifer SchaubEdgar A OttoJeffrey B HodginMatthias KretzlerChristopher AndertonTheodore AlexandrovDavid CherneySu Chi LimRobert G NelsonJonathan GelfondRavi Iyengarnull null
Published in: medRxiv : the preprint server for health sciences (2023)
Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality, however, few mechanistic biomarkers are available for high risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from Chronic Renal Insufficiency Cohort (CRIC), Singapore Study of Macro-Angiopathy and Reactivity in Type 2 Diabetes (SMART2D), and the Pima Indian Study determined if urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in CRIC (HR 1.57, 1.18, 2.10) and SMART2D (HR 1.77, 1.00, 3.12). ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in CRIC (HR 2.36, 1.26, 4.39), SMART2D (HR 2.39, 1.08, 5.29), and Pima Indian study (HR 4.57, CI 1.37-13.34). Empagliflozin lowered UAdCR in non-macroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology and transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mammalian target of rapamycin (mTOR). Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.
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