Elevated levels of soluble urokinase-type plasminogen activator receptor (suPAR) are associated with poor outcomes.
Chronic kidney disease (CKD) and progressive loss of kidney function affects about 11% of all Americans and put patients at higher risk for cardiovascular disease (CVD) and death. Screening for kidney disease is limited in that we rely on measuring urinary protein excretion and calculating estimated glomerular filtration rates (eGFRs). Unfortunately, proteinuria and decline in eGFRs are relatively insensitive identifiers of early injury and CKD. “Finding more sensitive biomarkers may help us identify at-risk patients earlier in the disease process and help us in the development of interventions for preventing progression to CKD,” says Jochen Reiser, MD, PhD.
Recent studies suggest that elevated levels of soluble urokinase-type plasminogen activator receptor (suPAR) are associated with poor outcomes in various patient populations. In addition, suPAR has been implicated in the pathogenesis of kidney disease, specifically focal segmental glomerulosclerosis and diabetic nephropathy. It is thought that suPAR interferes with podocyte motility and viability. “Given the growing role for podocytes in the development of CKD, these findings indicate that there may be a more general role for suPAR in kidney disease,” says Dr. Reiser.
A Closer Look
In a large, prospective cohort study involving patients with risk for CVD published in New England Journal of Medicine, Dr. Reiser and colleagues tested the hypothesis that plasma suPAR levels are associated with new-onset CKD. Plasma suPAR levels were measured in more than 3,600 patients who were enrolled in the Emory Cardiovascular Biobank. The study group determined renal function at enrollment and at subsequent visits in 2,292 participants and examined the relationship between suPAR levels and eGFR at baseline, changes in eGFR over time, and the development of CKD.
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“Elevated suPAR levels were associated with incident CKD and a more rapid decline in the eGFR in people who had normal kidney function at baseline,” says Dr. Reiser. The 921 participants with a normal eGFR (≥90 ml per minute per 1.73 m2) at baseline had the largest suPAR-related decline in the eGFR. In 1,335 participants with a baseline eGFR of at least 60 ml per minute per 1.73 m2, the risk of progression to CKD in the highest quartile of suPAR levels was 3.13 times as high as that seen in the lowest quartile. “Our findings were corrected for and found to be independent of conventional risk factors for kidney disease and CVD,” adds Dr. Reiser.
The study also showed that including suPAR levels in a prediction model significantly improved discrimination of future risk of CKD when compared with using a standard clinical model, according to Dr. Reiser. “We found that suPAR was associated with a decline in renal function among younger people, a patient group that had a significantly lower burden of risk factors for CVD,” he says. “This suggests that the effect of suPAR is truly independent of traditional risk factors for CVD and CKD.”
The study notes that suPAR added significant prognostic value in all patients and in subgroups of participants who had diabetes or hypertension, two of the most prevalent diseases associated with CKD in the United States. The biomarker was also associated with CKD in both whites and blacks, despite the marked differences between these two racial groups in the likelihood of CKD.
“Measuring suPAR may allow for more accurate stratification of patients early in their disease course, and with all we know, it is reasonable to suggest that suPAR may be causally implicated in various renal diseases,” Dr. Reiser says. “Anti-suPAR treatments have potential to treat kidney diseases more effectively and will also enable us to rationally target preventive health resources. In addition, such we may be able to enroll patients into potential trials of new renal-protective therapies by selecting those who are at highest risk for CKD or CKD progression.”
Hayek SS, Sever S, Trachtman H, et al. Soluble urokinase receptor and chronic kidney disease. N Engl J Med. 2015;373:1916-1925. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1506362#t=article. For a press release on this study, go to https://www.rush.edu/news/press-releases/early-warning-found-chronic-kidney-disease.
James MT, Hemmelgarn BR, Tonelli M. Early recognition and prevention of chronic kidney disease. Lancet. 2010;375:1296-1309.
Thunø M, Macho B, Eugen-Olsen J. suPAR: the molecular crystal ball. Dis Markers. 2009;27:157-172.
Fox CS, Larson MG, Leip EP, Culleton B, Wilson PWF, Levy D. Predictors of new-onset kidney disease in a community-based population. JAMA. 2004;291:844-850.