New, Early Marker of Kidney Disease Said to Predict Development of CKD

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The inflammatory/immune biomarker soluble urokinase receptor (suPAR) may offer a valuable new tool for identifying patients at increased risk of chronic kidney disease (CKD), according to a study in The New England Journal of Medicine.

“SuPAR promises to do for kidney disease what cholesterol has done for cardiovascular disease,” commented senior author Jochen Reiser, MD, PhD, who is Ralph C. Brown, MD, professor and chairman of medicine at Rush University Medical Center in Chicago.

Lead researchers Salim Hayek, MD, and Arshed Quyyumi, MD, both at Emory University, Atlanta, measured suPAR in 3683 individuals from the Emory Cardiovascular Biobank, a prospective registry of patients undergoing cardiac catheterization. Median age was 63 years; about two-thirds of those studied were men.

In this cohort of patients with cardiovascular disease, the median suPAR level was 3040 pg/mL. As a group, patients with higher suPAR levels had a lower estimated glomerular filtration rate and a higher rate of proteinuria.

SuPAR was then evaluated for association with change in eGFR over time and with incident CKD in 2292 participants. In adjusted models, higher baseline suPAR was associated with a faster decline in eGFR: median annual change -4.2 mL/min/1.73 m2 for those in the highest quartile of suPAR versus -0.9 mL/min/1.73 m2 for those in the lowest quartile. Five-year decline in eGFR was about 20 percent for subjects in the highest quartile of suPAR and 15 percent for those in the third quartile, compared to 7 percent in the two lower quartiles.

The suPAR-related decline in eGFR was greatest among subjects with a normal baseline value (greater than 90 mL/min/1.73 m2). The association was independent of race, diabetes, or proteinuria.

Of 1335 participants with a normal baseline eGFR (60 mL/min/1.73 m2), 24 percent developed CKD during follow-up. Relative to the lowest quartile of suPAR, risk of CKD was about three times higher for subjects in the highest quartile and twice as high for those in the third quartile.

Forty percent of patients with suPAR levels above the median developed CKD, compared to 10 percent of those with lower levels. For subjects with very high suPAR levels—greater than 4020 pg/mL—estimated 10-year risk of CKD was about 80 percent.

In validation studies in a cohort of women from the Women’s Interagency HIV Study, the association between suPAR and kidney disease was still significant, but weaker. This likely reflected the younger age and better health of women in the validation group.

SuPAR, as well as its membrane-bound form, plays a direct role in regulating cell adhesion and migration via integrin binding. Reiser’s lab has previously presented evidence that suPAR is involved as a circulating blood factor in the pathogenesis of focal segmental glomerulosclerosis and diabetic kidney disease. These findings prompted the researchers to suspect that suPAR may play a broader role in the development of CKD.

Could suPAR testing to assess kidney disease risk really become as familiar as cholesterol testing for cardiovascular disease risk? While not yet FDA-approved for use in direct patient care, the suPAR blood tests are relatively inexpensive and are already being used in Europe for other purposes.

“One characteristic of suPAR is that it is unmodifiable to some degree by lifestyle— for example by stopping [smoking],” said Reiser. “Also, if suPAR is high, we can particularly watch those patients and be more aggressive in terms of giving proper medications to control high blood pressure and diabetes, which contribute to CKD.”

Sanja Sever, PhD, co-first author of the study, commented: “SuPAR testing could also be useful for stratifying nephropathy risk in patients with diabetes—for example, in clinical trials testing nephropathy drugs.” Sever is associated with Harvard Medical School.

Hayek and Reiser agree as to the next steps toward routine testing of suPAR:

  • Exploring whether a change in suPAR is associated with reclassification of risk
  • Determining what lifestyle or therapeutic measures lead to a change in suPAR levels
  • Designing a trial in which subjects are randomized according to their suPAR levels to usual care versus therapies shown to modify suPAR

Answers to these points will also provide insights as to whether suPAR might be a new therapeutic target in CKD. If so, “We may envision an injectable antibody that binds to suPAR and basically neutralizes it,” Reiser said.