Complement protein in urine may help predict AAV kidney flare

High complement system fragment Ba levels may serve as predictive biomarker

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A dropper is seen squirting blood alongside four half-filled vials of blood.

A protein fragment called Ba that’s produced when the alternative complement pathway is activated is found at high levels in the urine of people with ANCA-associated vasculitis (AAV) during a kidney flare, a small study suggests. This means it may serve as a biomarker for predicting and monitoring kidney-related disease activity.

The study, “Urine and Plasma Complement Ba Levels During Disease Flares in Patients with ANCA-Associated Vasculitis,” was published in Kidney International Reports.

Part of the body’s immune system, the complement cascade is made up of proteins that work through a domino-like series of molecular events, with the activation of one promoting the activation of another, and so on.

The pathway’s overactivation is thought to contribute to AAV, a group of diseases marked by the production of self-reactive antibodies against a type of immune cell that leads to inflammation in small blood vessels and damage to several tissues and organs, most commonly the kidneys and lungs.

How exactly the complement pathway is implicated in AAV remains unclear. Several complement proteins have been found at high levels in people with active AAV and with AAV-related kidney damage.

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What is the complement protein Ba?

There’s limited evidence on the dynamics of the levels of complement proteins over time in AAV, “the relationship between the [blood] and urine levels of these markers, and their specificity for kidney involvement,” wrote researchers in the U.S., who analyzed the urine and blood levels of the complement fragment Ba in 60 people with a diagnosis of AAV and at different disease states.

Ba results from the activation of the alternative complement pathway, which, unlike the antibody-activated classic pathway, is made active by foreign invaders such as bacteria and other microorganisms. Microbial infections are also thought to be a trigger of AAV.

Urine and blood samples were collected during 233 visits over a median of 21 months, or nearly two years. Patients’ mean age was 54 and little over half (53%) were men. Most (93%) were white. A total of 21 patients had worsening kidney symptoms, or a flare, while 19 had a flare not related to the kidneys. The remaining 20 patients were in long-term remission, meaning they showed no symptoms on three to four consecutive visits and were included as controls.

“At the time of a flare, most patients in the [kidney flare] and [non-kidney flare] had ear/nose/throat and pulmonary involvement,” the researchers wrote.

The higher the levels of Ba in urine, the higher those in blood, across all patient groups, but the strength of this association varied, results showed.

“The correlation was strong at the time of a renal [kidney] flare, modest at the time of a non-renal flare, and poor when vasculitis was in remission,” the researchers wrote, adding that “correlations between [blood] and urine complement Ba levels were found to depend on kidney involvement.”

Urine Ba levels and kidney flares

Urine Ba levels were on average about three times as high at the time of a kidney flare relative to the timepoints leading to a relapse, but remained stable during a non-kidney flare. Patients in long-term remission also showed stable urine Ba levels over time. Blood Ba levels remained stable over time in all groups.

Urine and blood Ba levels measured at the time of a kidney flare, as well as their change from the visit before the kidney flare, could predict a kidney flare. Urine Ba levels at the time of a kidney flare showed the best predictive potential.

When measured at the time of a kidney flare, levels greater than 12.53 nanograms per milligram of urine creatinine could predict a kidney flare with a sensitivity of 76.2% and a specificity of 68.4%. Sensitivity refers to how well the test can predict a kidney flare in those who actually had one. Specificity refers to the proportion of patients correctly identified as not having a kidney flare. Creatinine is a waste product that helps indicate how well the kidneys are working and was used to correct Ba levels by kidney function.

The results “do not support the utility of plasma or urine Ba as biomarkers of nonrenal flares … In contrast, urine Ba levels increased at the time of a renal flare, identifying it as a promising biomarker for renal vasculitis activity,” the researchers wrote. “The implications of those observations are intriguing and may suggest that patients with renal involvement may have a more pronounced degree of complement activation than those with nonrenal vasculitis and that [whole-body] complement activity may be more dependent on the organs involved rather than the disease severity.”

However, “there was significant variation in [blood] plasma and urine Ba levels between patients at the time of a renal flare, suggesting the intensity of complement activation may be different between patients,” they wrote, noting “urine Ba levels are potential biomarkers for acute changes in renal activity” with AAV. They said their results should be validated in other AAV before being developed for clinical use.