Urine levels of adenine, a metabolite produced in the kidney, are predictive and a causative biomarker of looming progressive kidney failure in patients with diabetes, a finding that could lead to earlier diagnosis and intervention, researchers from The University of Texas Health Science Center at San Antonio (also called UT Health San Antonio) reported Aug. 24 in the Journal of Clinical Investigation. Elevated adenine was also associated with all-cause mortality.
The study results are significant because until now, the most important marker for kidney disease has been protein (or albumin) in the urine.
Up to half of diabetes patients who develop kidney failure never have much protein in their urine. As 90% of patients with diabetes (more than 37 million patients in the U.S.) remain at increased risk despite low levels of albumin in their urine, this study has widespread consequences. It is the first study to identify these patients at an early stage by measuring this new causative marker in the urine.
The finding paves the way for clinic testing to determine — five to 10 years before kidney failure — that a patient is at risk, said the senior study author, Kumar Sharma, MD.
Importantly, the research team identified a small molecule that blocks the major pathway of endogenous adenine production in the body. This therapeutic drug reduced kidney adenine levels in mice with type 2 diabetes.
The team found endogenous adenine around scarred blood vessels in the kidney and around tubular-shaped kidney cells that were being destroyed. Endogenous substances are those that naturally occur in the body.
The finding that high levels of adenine were also associated with all-cause mortality in the study participants suggests that the metabolite is affecting other parts of the body, as well, Sharma said.
Many patients with diabetes know they’re at risk of kidney disease, but if they don’t have protein in their urine, they think they are protected, he said.
Although treatments to protect against diabetes and blood pressure are improving, they only push the envelope a little bit, Sharma said, in that patients still have progressive kidney disease and kidney failure, but they are afforded more time before they reach that endpoint. The measurement of urine adenine is difficult; however, the team at the Center for Precision Medicine at UT Health San Antonio has developed a robust and sensitive method to measure urine adenine in patients.
Kumar Sharma, Guanshi Zhang, Jens Hansen, Petter Bjornstad, Hak Joo Lee, Rajasree Menon, Leila Hejazi, Jian-Jun Liu, Anthony Franzone, Helen C. Looker, Byeong Yeob Choi, Roman Fernandez, Manjeri A. Venkatachalam, Luxcia Kugathasan, Vikas S. Sridhar, Loki Natarajan, Jing Zhang, Varun S. Sharma, Brian Kwan, Sushrut S. Waikar, Jonathan Himmelfarb, Katherine R. Tuttle, Bryan Kestenbaum, Tobias Fuhrer, Harold Feldman, Ian H. de Boer, Fabio C. Tucci, John Sedor, Hiddo Lambers Heerspink, Jennifer Schaub, Edgar A. Otto, Jeffrey B. Hodgin, Matthias Kretzler, Christopher R. Anderton, Theodore Alexandrov, David Cherney, Su Chi Lim, Robert G. Nelson, Jonathan Gelfond, Ravi Iyengar. Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients. Journal of Clinical Investigation, 2023; DOI: 10.1172/JCI170341
University of Texas Health Science Center at San Antonio. (2023, August 24). Metabolite in urine predicts diabetic kidney failure 5-10 years early; oral therapeutic drug shows promise in mice. ScienceDaily. Retrieved August 25, 2023 from www.sciencedaily.com/releases/2023/08/230824120209.htm
Photo by Mikhail Nilov from Pexels: https://www.pexels.com/photo/close-up-shot-of-a-black-glucometer-beside-a-syringe-8669957/