Tiny RNA molecules carried by extracellular vesicles in the bloodstream can accurately predict kidney function decline and cardiovascular risk in chronic kidney disease (CKD), as reported by researchers from Science Tokyo. By analyzing blood samples from a large cohort, the team identified multiple microRNAs linked to disease progression and built a model to distinguish high-risk patients with CKD. Clinically applying this risk score model can contribute to improved patient outcomes.
Chronic kidney disease (CKD) has become one of the world's fastest growing threats to public health, affecting more than 850 million people globally. While the condition is widely known for gradually impairing kidney function, many patients die prematurely from cardiovascular complications long before they ever require dialysis or transplantation. Managing the disease is further complicated by the fact that kidney function does not usually decline at a uniform rate. This unpredictable progression makes it hard for doctors to identify which individuals are at high risk, often leading to delayed interventions.
Unfortunately, current tools used to monitor CKD rely heavily on biomarkers such as protein levels in urine (proteinuria) or glomerular filtration rate to assess kidney function, which share notable limitations. While these measurements reflect existing kidney damage, they do not capture the finer molecular changes that link kidney dysfunction to harm in other organs, such as the heart. Thus, there is an urgent need for novel, minimally invasive biomarkers that can accurately forecast both kidney decline and the risk of cardiovascular complications linked to CKD.
Against this backdrop, a research team led by a third-year doctoral student Shunsuke Inaba and Associate Professor Shintaro Mandai from the Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo (Science Tokyo), Japan, in collaboration with Associate Professor Takanori Hasegawa of the M&D Data Science Center, Institute of Integrated Research, Science Tokyo, investigated whether tiny RNA molecules found in the bloodstream could serve as predictive biomarkers for CKD outcomes. Their work, made available online on December 10, 2025, and published in Volume 15, Issue 1 of the Journal of the American Heart Association on January 06, 2026, explores how these microRNAs (miRNAs) reflect systemic biological changes linking kidney and cardiovascular disease.
The team focused on miRNAs found in circulating extracellular vesicles (cEVs), which are nanoscale membrane-bound vesicles naturally released by cells. Once considered cellular debris, they are now recognized as carriers of biologically active molecules that enable communication between distant organs. Because these vesicles protect their molecular cargo from degradation, they provide a stable source of information about disease processes occurring throughout the body.
In an initial cohort of 36 patients, the researchers identified 23 miRNAs that were significantly depleted in cEVs in advanced CKD. Many of these miRNAs regulate pathways involved in vascular remodeling, inflammation, metabolic alterations, and cellular aging—processes that can drive both kidney damage and cardiovascular risks. "We theorized the reduction of these miRNAs in EVs may play a role in the pathophysiology of the underlying mechanisms of CKD and its cardiovascular associations," explains Inaba.
Using statistical modeling and machine learning, the team narrowed the results to three key miRNAs that most strongly predicted kidney decline and validated them in a cohort of 234 patients with CKD. They combined these new biomarkers with cystatin C and urinary protein-to-creatinine ratio measurements to develop an integrated risk model, which they called the 'M3V2 equation.'
As revealed by a long-term follow-up lasting several years, the new model significantly outperformed conventional clinical markers and existing risk classification tools in predicting both kidney decline and major cardiovascular events. Interestingly, it was effective regardless of the underlying cause of CKD or the presence of cardiovascular disease. "Our results strongly demonstrate the robustness and flexibility of the optimized M3V2 equation in predicting kidney outcomes as well as clinically important composite events in patients with CKD," notes Inaba.
Taken together, the findings of this study shed light on how miRNA signaling between cells and its reduction are tightly linked to the systemic progression of pathologies like CKD. These findings also support the emerging axis of cardiovascular-kidney-metabolic syndrome. Further research efforts on this topic will help advance personalized medicine for people with kidney disease, thus preventing unnecessary complications and deaths.
