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suPAR—an early warning signal

One important aspect of research on inflammation in HIV is the ability to monitor inflammation. Researchers in Copenhagen, Denmark, have been studying levels of a protein that is released into the blood of people. This protein, called suPAR (soluble urokinase plasminogen activator receptor), is released during chronic inflammation. In a study of more than 900 HIV-positive people, the researchers have found that having an elevated level of suPAR at the start of the study was linked to an increased risk for subsequent serious health problems as well as diminished survival. Further research on suPAR in people with HIV is underway in Denmark and the U.S.

About suPAR

Before discussing suPAR we first explain its precursor, uPAR (urokinase plasminogen activator receptor). uPAR is a protein found mainly on activated cells of the immune system, including the following:

  • T-cells
  • neutrophils
  • macrophages

When inflammation occurs, these cells release uPAR into circulation, where it is called soluble uPAR, or suPAR. Many studies have found a connection between high levels of suPAR and a range of health conditions in which inflammation is involved and injury to major organ-systems is involved in HIV-negative people. In HIV-positive people, studies have found that the highest levels of suPAR occur in AIDS and high levels are linked to diminished survival.

Study details

Researchers collaborated with Denmark’s ongoing HIV observational database. They analysed blood samples collected in 2007 (the start of the study) and monitored participants until May 2015, assessing what complications subsequently developed.

A total of 947 participants were in this study. Their average profile upon entering the study was as follows:

  • age – 45 years
  • 73% men, 27% women
  • 46% were gay or bisexual men
  • suPAR level – 2.65 ng/mL

On average, participants were in the study for seven years.

Results—New health conditions

A total of 270 diagnoses of complications all unrelated to HIV were made after the start of the study, grouped as follows:

  • cardiovascular disease – 68 cases
  • cancer – 66 cases
  • chronic lung disease – 56 cases
  • diabetes – 34 cases
  • chronic kidney disease – 23 cases
  • chronic liver disease – 23 cases

Statistical analysis found that participants with high levels of suPAR at the start of the study were significantly more likely to get these conditions (except for diabetes).

suPAR and survival

During the study, 121 (13%) participants died. These people had significantly higher levels of suPAR at the start of the study (4.09 ng/mL) than people who survived (2.56 ng/mL).

Researchers found that for every 1 ng/mL increase in suPAR levels, there was a 23% increased risk for dying. Researchers divided people into four groups or “quartiles” based on their suPAR levels (the first 25%, or quartile, had the lowest suPAR levels and the final 25%, or fourth quartile, had the highest levels). They found that people in the upper quartile had a six-fold increased risk of death compared to people in the lowest quartile.

Bear in mind

1. Additional risk factors

This prospective study has shown a relationship between elevated suPAR levels and an increased risk for a range of complications and death all unrelated to HIV disease. The relationship between elevated suPAR levels and these unfortunate outcomes was still valid, particularly in the case of cardiovascular disease, after researchers took into account factors that incite inflammation, including smoking and injecting street drugs.

2. Populations

When researchers segregated participants by suPAR level and how they acquired HIV, they found that the ability of suPAR to predict future unfortunate events was “strongest in individuals with no other potential drivers of inflammation such as injecting street drugs and smoking.”

The role of suPAR

As the researchers did not conduct additional monitoring of other proteins associated with inflammation (such as interleulin-6, CD14, CD163) and lab studies of cells and suPAR, it is not clear if suPAR is merely a marker for future unfortunate events or plays some role in directly causing inflammation.

What’s next for suPAR

Researchers with the U.S.-based ACTG (AIDS Clinical Trials Group) have been conducting a study of suPAR and will release their results in 2018. Additional studies with suPAR are underway in that country.

In Denmark, researchers are continuing to study suPAR in people with HIV who initiate ART and achieve an undetectable viral load and are comparing their suPAR levels to those of HIV-negative people.

suPAR has much potential as a tool to monitor the health of people and high levels of this protein indicate that there are likely problems to come.

Acknowledgement

We thank Jesper Eugen-Olsen, PhD, University of Copenhagen, Denmark, for helpful discussion, research assistance and expert review.

—Sean R. Hosein

REFERENCES:

  1. Kirkegaard-Klitbo DM, Langkilde A, Mejer N, et al. Soluble urokinase plasminogen activator receptor is a predictor of incident non-AIDS comorbidity and all-cause aortality in human immunodeficiency virus type 1 infection. Journal of Infectious Diseases. 2017 Oct 17;216(7):819-823.
  2. Desmedt S, Desmedt V, Delanghe JR, et al. The intriguing role of soluble urokinase receptor in inflammatory diseases. Critical Reviews in Clinical Laboratory Sciences. 2017 Mar;54(2):117-133.
  3. Rasmussen LJ, Knudsen A, Katzenstein TL, et al. Soluble urokinase plasminogen activator receptor (suPAR) is a novel, independent predictive marker of myocardial infarction in HIV-1-infected patients: a nested case-control study. HIV Medicine. 2016 May;17(5):350-7.