CKD: Elevated Plasma SuPAR Levels May Signal Trouble

Marcia Frellick

November 05, 2015

Researchers have identified soluble urokinase-type plasminogen activator receptor (suPAR) levels as a potential biomarker for chronic kidney disease (CKD).

Salim S. Hayek, MD, from the Division of Cardiology, Emory Clinical Cardiovascular Research Institute at Emory University School of Medicine in Atlanta, Georgia, and colleagues found an association between elevated plasma of suPAR and both a decline in the estimated glomerular filtration rate (eGFR) in persons with normal kidney function at baseline and the development of CKD.

These findings were published online November 5 in the New England Journal of Medicine and presented at Kidney Week in San Diego.

An accompanying editorial says the study demonstrates the potential of suPAR plasma levels as a biomarker, but more studies would be necessary to cement that connection.

Plasma suPAR levels were measured in 3683 people enrolled in the Emory Cardiovascular Biobank, a prospective registry of patients undergoing cardiac catheterization at three Emory Healthcare sites in Atlanta between 2003 and 2009. Researchers determined renal function at enrollment and at subsequent visits in 2292 people.

Results Are Significant, Consistent

A higher suPAR level at baseline was linked with a greater decline in the eGFR at follow-up; the annual eGFR change was −0.9 mL/minute per 1.73 m2 among participants in the lowest quartile of suPAR levels compared with −4.2 mL/minute per 1.73 m2 among participants in the highest quartile (P < .001).

In 1335 participants with a baseline eGFR of at least 60 mL/minute per 1.73 m2, the risk for incident CKD among patients in the highest quartile of suPAR levels was 3.13 times as high (95% confidence interval, 2.11 - 4.65 times) as the risk among those in the lowest quartile.

Data from the study suggest that suPAR meets some of the critical criteria for biomarkers, including that higher suPAR levels were associated with CKD in both whites and blacks, despite the substantial differences between these two groups in the likelihood of CKD.

Identifying a biomarker that would signal CKD early, when renal function is well-preserved and medical interventions would stand a good chance of slowing disease, would be an important finding. Although many biomarkers are being explored, the authors say, "none have been shown to predict the incidence of [CKD] in patients with a normal eGFR."

At this time, screening for kidney disease is limited to measurement of urinary protein excretion and calculation of the eGFR. Albuminuria and decreased renal function are detected only after substantial kidney damage.

"Early identification and management of [CKD] is highly cost-effective and can reduce the risk of progression to [CKD] and cardiovascular disease by up to 50%," the authors write.

More Precise Measurements Needed

In an accompanying editorial, Karl L. Skorecki, MD, from the Rappaport Faculty of Medicine, Technion-Israel Institute of Technology in Haifa, and Barry I. Freedman, MD, from the Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, note that the study has many strengths. The study design is complex, and the authors tested their findings on two randomly selected subgroups of the Emory Cardiovascular Biobank cohort, as well as with a different assay in a subgroup of women in the Women's Interagency HIV Study cohort, and findings were consistent in these disparate groups.

"However, it had only semiquantitative measurement of proteinuria and lacks corresponding accurate measures of urinary protein excretion, which would be important in studying a factor that increases glomerular permeability; thus, risk discrimination may not have been able to dissect interactions between increasing albuminuria and a decline in kidney function," they write. The authors also acknowledge the limitations on proteinuria measurement.

Therefore, they write, whether kidney disease caused elevated suPAR levels is uncertain. They called for further study of associations with proteinuria, as well as relationships among plasma suPAR levels, proteinuria, and progression to CKD, and more precise measurements of albuminuria.

The study was funded by the Abraham J. and Phyllis Katz Foundation, Emory Heart and Vascular Center, and National Institutes of Health, One coauthor reported receiving grant support from the National Institute of Health, Nephcure, and Thermo BCT; personal fees from Astellas, Massachusetts General Hospital, Genentech, UpToDate, Merck, and Questcor; and other support from TRISAQ, as well as having patents related to suPAR in diabetic kidney disease, reducing soluble urokinase receptor in the circulation, the treatment of renal disease, the role of suPAR in the pathogenesis of proteinuric kidney disease, and methods, and compositions for the treatment of proteinuric diseases, all issued to TRISAQ. Another coauthor reported receiving personal fees from Questcor and other support from TRISAQ, as well as a pending patent related to the role of suPAR in the pathogenesis of proteinuric kidney disease licensed to TRISAQ. Another coauthor reported receiving personal fees from Kaneka and Otsuka and other support from Bristol-Myers Squibb. Another coauthor reported receiving grant support from Mallinkrodt Pharmaceuticals. Another coauthor reported receiving grant support from Thermo BCT and a pending patent related to a SuPAR in diabetic kidney disease licensed to TRISAQ. The other authors have disclosed no relevant financial relationships. Dr Freedman reported receiving grant support from Novartis. Dr Skorecki has disclosed no relevant financial relationships.

N Engl J Med. Published online November 5, 2015. Article full text, Editorial full text

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