A growing body of scientific evidence suggests that a single immune-derived protein—soluble urokinase plasminogen activator receptor (suPAR)—may be a key biological link connecting kidney disease, cardiovascular disease, and diabetes. Researchers report that suPAR is not only a marker of inflammation but may actively contribute to organ damage across multiple systems.

In a recent review published in the Journal of Clinical Investigation, scientists examined how uPAR and its circulating fragments influence chronic inflammation and drive injury in the kidneys, heart, and pancreas. The findings offer new insight into why these conditions so often coexist and progress together.

The Immune System’s Role in Multiorgan Disease

Chronic activation of the innate immune system is a defining feature of many major diseases, including chronic kidney disease (CKD), cardiovascular disease (CVD), and diabetes. Conditions such as hypertension, obesity, infections, smoking, and metabolic stress can trigger immune dysregulation, leading to persistently elevated levels of suPAR.

uPAR is a membrane-bound receptor found on immune and endothelial cells, where it regulates immune activation, cell adhesion, and tissue remodeling. When cleaved from the cell surface, uPAR forms circulating proteins including suPAR and smaller fragments such as D2D3, which are increasingly recognized as biologically active mediators of disease.

suPAR and Kidney Disease Progression

Numerous clinical studies show that elevated suPAR levels are strongly associated with declining kidney function. Individuals with high suPAR concentrations experience faster loss of estimated glomerular filtration rate (eGFR) and a significantly higher risk of progressing to chronic kidney disease—even when kidney function appears normal at baseline.

Genetic studies further support a causal role. Variants in the PLAUR gene, which encodes uPAR, are associated with higher circulating suPAR levels and increased risks of CKD and atherosclerosis. Unlike traditional kidney markers, suPAR reflects systemic immune activation rather than kidney-specific injury, helping explain its strong predictive value.

Despite these findings, clinical use of suPAR remains limited due to assay variability and the lack of standardized testing methods.

Beyond the Kidneys: Diabetes and Acute Kidney Injury

Experimental data suggest that suPAR directly alters kidney tubular cell metabolism, increasing mitochondrial stress and vulnerability to injury. Clinically, high suPAR levels are linked to an increased risk of acute kidney injury (AKI), particularly in patients undergoing cardiac procedures or experiencing sepsis.

The uPAR fragment D2D3 appears to play an additional role in metabolic disease. Animal models show that excess D2D3 can trigger both progressive kidney damage and insulin-dependent diabetes. Laboratory and human islet studies reveal that D2D3 interferes with insulin secretion, highlighting a potential immune-mediated pathway linking diabetes and kidney disease.

suPAR as a Predictor of Cardiovascular Risk

Elevated suPAR levels have consistently been associated with subclinical atherosclerosis, heart failure, myocardial infarction, and peripheral artery disease. Unlike traditional inflammatory markers such as C-reactive protein, suPAR levels remain stable during acute illness and show minimal daily fluctuation, making them a reliable indicator of long-term cardiovascular risk.

Mendelian randomization studies using PLAUR gene variants suggest that higher suPAR levels may directly increase the risk of cardiovascular events, reinforcing the idea that suPAR is more than a passive biomarker.

Therapeutic Potential and Future Directions

Currently, no approved therapies specifically target suPAR or uPAR signaling. However, an anti-suPAR monoclonal antibody (WAL0921) is undergoing phase II clinical trials, signaling growing interest in translating these findings into treatment strategies.

Researchers emphasize that further human interventional studies are needed to determine whether lowering suPAR levels or blocking uPAR-derived signaling can slow or prevent disease progression across organ systems.

A Unifying Link Across Chronic Diseases

The emerging evidence positions suPAR as a unifying biological factor linking kidney disease, heart disease, and diabetes through immune-driven inflammation. As research advances, uPAR-related proteins may become valuable tools for early risk assessment—and potentially, targets for therapy—in a wide range of chronic inflammatory and cardiometabolic disorders.

Source: https://www.news-medical.net/news/20260106/A-single-immune-protein-may-help-explain-why-kidney-and-heart-disease-often-develop-together.aspx