Researchers have found a new biomarker in urine – other than albumin – that could help with diagnosing kidney failure five to 10 years early, hopefully leading to new diagnostic tools and treatments for kidney failure, they said.
Currently, albumin – a protein made by the liver – is considered an important diagnostic marker for kidney disease.
However, up to 50% of patients with diabetes with a high risk of chronic kidney disease (CKD) and kidney failure have low levels of albumin in their urine, reports MedicalNewsToday.
Now, say scientists, these new biomarkers for kidney failure could help clinicians diagnose and treat CKD before it progresses to later stages.
The researchers, led by by a team from the University of Texas, recently investigated whether urine levels of adenine, a metabolite produced by the kidney, could predict kidney disease in people with diabetes – and found that higher adenine levels were linked to higher rates of kidney failure.
High levels of adenine
They analysed urine sample data from more than 1 200 patients with diabetes and impaired kidney function from three international research cohorts.
In each of the cohorts, they found that higher levels of adenine were linked to higher rates of kidney failure. This also applied to patients with low levels of albumin in their urine.
The higher adenine levels were further linked to a higher risk of all-cause mortality, which researchers suggested means the metabolite might also affect other areas of the body.
In a further analysis, they honed in on adenine levels of a subset of 40 patients with type 1 diabetes who had been given empagliflozin, an anti-diabetic drug used to improve glucose control. After eight weeks of treatment, their adenine levels fell by 36.4%.
The researchers suggested that benefits from empagliflozin may be partly due to lower adenine levels. This idea is consistent with recent research, suggesting empagliflozin reduces the risk of CKD progression.
The study team further investigated whether modifying adenine levels affected kidney failure risk, testing a drug that blocks a major pathway of adenine production in mouse models of type 2 diabetes.
Ultimately, the drug both reduced adenine levels in the mice and protected them against kidney injury and thickening of kidney walls – known as kidney hypertrophy – without affecting blood sugar.
Last, the researchers conducted biopsies of kidneys from human patients with and without diabetes, using a new technique called spatial metabolomics. In doing so, they were able to determine the locations of adenine and other small molecules in kidney tissue.
Whereas low levels of adenine were present in healthy kidneys, they noted that adenine levels were elevated in certain areas of kidneys with diabetes, such as scarred blood vessels.
The study was published in The Journal of Clinical Investigation.
Limitations
Dr Donald Molony, distinguished teaching professor of the University of Texas System at McGovern Medical School University, who was not involved in the study, said the study had very few limitations and the design was robust, with a “low risk of scientific bias”.
“Its most important implication is that we now have a powerful biomarker that might allow us to identify individuals with early CKD at risk for disease progression.”
While previous studies confirm the validity of adenine levels as a biomarker, he said, they don’t necessarily present a causative link between adenine and CKD. He noted, however, that this study strongly suggests that high urinary adenine levels may, at least in part, cause kidney failure.
“A significant portion of (the participants did) not have traditional clinical markers of CKD. They had healthy kidney clearance function and no abnormal protein in the urine. Currently, they would not be candidates for adenine-lowering drugs due to their kidney function and absence of excess protein in their urine,” Molony said.
The study serves as evidence to introduce adenine-lowering drugs or other kidney protective interventions early on in treatment “that might otherwise not be considered until [excess protein occurs in the urine] or there is a rise in blood creatinine”.
“It also opens up an entirely novel target for the development of therapeutics that might reduce progression to kidney failure,” he added, and serves as evidence to introduce adenine-lowering drugs or other kidney protective interventions early on in treatment “that might otherwise not be considered until [excess protein occurs in the urine] or there is a rise in blood creatinine”.
“It also opens up an entirely novel target for the development of therapeutics that might reduce progression to kidney failure,” he added.
However, Dr Jared Braunstein, board certified internist with Medical Offices of Manhattan, who was not involved in the study, said the study was limited as most of its data came from lab animals, as opposed to humans. He added that its small sample size also reduced the “power” of the study.
Dr Shuta Ishibe, professor of nephrology at Yale School of Medicine, also not involved in the study, suggested that “further investigation is required to determine whether endogenous adenine production contributes to the progression of (diabetic kidney disease) (DKD), or just serves as a biomarker, or potentially a combination of both”.
Study details
Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients
Kumar Sharma, Guanshi Zhang, Jens Hansen, Ravi Iyengar et al.
Published in The Journal of Clinical Investigation on 24 August 2023
Abstract
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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