Proteomic Blood Test Predicts Kidney Failure in APOL1 High-Risk Individuals Years Before Symptoms Emerge
核心洞察
A nine-protein blood-based risk score (APRS) developed at Penn Medicine predicts kidney failure (搜索) up to ten years before clinical symptoms in individuals of African ancestry carrying high-risk APOL1 (搜索) variants.
More than 60% of individuals in the highest-risk category progressed to kidney failure (搜索) requiring dialysis or transplantation within a decade, compared to fewer than 1% in the lowest-risk group.
The APRS outperformed existing clinical prediction tools including the Kidney Failure (搜索) Risk Equation (KFRE) and was validated in independent U.S. and U.K. cohorts.
A research team from the Perelman School of Medicine at the University of Pennsylvania (搜索) has developed a blood test that can identify which individuals of African ancestry carrying high-risk APOL1 (搜索) gene variants are most likely to progress to kidney failure (搜索)—years before any clinical signs become apparent. The findings, published in Nature Medicine, represent a significant advance in risk stratification for a population that develops kidney failure at nearly four times the rate of those of European ancestry.
The APOL1 (搜索) gene confers protection against certain infections, but specific variants also substantially increase the risk of serious kidney disease. An estimated 4 to 5 million people in the United States carry these high-risk variants, yet most will never develop kidney disease. Until now, no reliable method existed to distinguish those truly at risk before kidney function begins to decline.
"What has been missing is a way to identify early disease activity before we see changes in standard clinical measures," said Katalin Susztak, MD, PhD, senior author of the study, professor in Renal Electrolyte and Hypertension, and director of the Penn/CHOP Kidney Innovation Center. "This approach allows us to intervene early enough and lessen the severity, or even prevent, kidney disease in some patients."
Deriving the APOL1 (搜索) Proteomic Risk Score
The researchers, led by Chenyu Li and colleagues, performed proteomic profiling of blood plasma samples from 1,113 Penn Medicine BioBank (搜索) participants with a high-risk APOL1 (搜索) genotype, including 851 individuals with preserved kidney function at the time of sample collection as inferred from estimated glomerular filtration rate (eGFR). Using an elastic net Cox regression model with cross-validation, the team derived a nine-protein signature that predicted risk of kidney disease progression independent of other clinical parameters.
This nine-protein signature was then combined with clinical variables to create the APOL1 (搜索) proteomic risk score (APRS). The proteins included in the score are linked to pathways involved in kidney injury and fibrosis, suggesting the test captures early biological changes that precede measurable loss of kidney function.
Striking Differences in Outcomes
The differences between risk categories were substantial. More than 60 percent of individuals in the highest-risk category experienced renal failure requiring dialysis or transplantation within ten years, compared to fewer than 1 percent in the lowest-risk group.
The findings were validated in two independent cohorts in the United States and the United Kingdom. Across all populations studied, the APRS consistently outperformed existing clinical prediction tools, including the Kidney Failure (搜索) Risk Equation (KFRE), the Chronic Renal Insufficiency Cohort (CRIC) proteomic score, and a chronic kidney disease polygenic risk score.
Clinical Implications and Therapeutic Relevance
The work aligns with a growing body of research demonstrating that circulating protein markers can reflect underlying tissue-level injury and disease progression. Together, these approaches are helping to move risk assessment in kidney disease beyond traditional clinical measures toward more direct readouts of disease biology.
Researchers say the test could be incorporated into routine care to guide monitoring and treatment decisions, particularly as therapies targeting APOL1 (搜索)-associated disease continue to advance. Several such therapies are currently in development, including experimental drugs designed to block the harmful effects of high-risk APOL1 variants in the kidney, with the goal of slowing or preventing kidney damage.
"One of the challenges in developing new therapies has been identifying the right patients early enough," Susztak said. "This provides a way to focus treatment on those most likely to benefit."
The team is now working toward bringing the test into the clinic and evaluating how patients' scores could support both individual patient care and the design of future clinical trials.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (DK076077, R01 DK087635, and R01 DK105821) and the National Heart, Lung, and Blood Institute (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005).