Urinary C5a may help flag kidney disease severity in ANCA vasculitis
Higher levels were linked to worse kidney outcomes, more severe biopsy findings
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Higher levels of the complement protein C5a in urine may provide a noninvasive way of identifying more severe kidney involvement and a greater likelihood of poor outcomes in people with ANCA-associated vasculitis (AAV), a study suggests.
In an unadjusted analysis, high urinary C5a was associated with a 3.73-fold higher risk of progressing to end-stage kidney disease requiring long-term dialysis, or death during follow-up.
Overall, these findings suggest that “urinary C5a may be [a] complementary noninvasive biomarker for assessing renal disease severity in AAV,” the researchers wrote.
The study, “Urinary C5a as a Noninvasive Marker of Renal Activity, Histopathological Severity, and Outcomes in ANCA-Associated Vasculitis,” was published in Kidney360.
AAV can cause serious kidney damage
AAV is a group of autoimmune diseases characterized by inflammation and damage to small blood vessels. These diseases are driven in part by self-reactive antibodies called ANCAs. The kidneys are commonly affected, and severe inflammation can lead to rapidly worsening kidney function and, in some patients, end-stage kidney disease.
An important driver of AAV is the complement system, a group of proteins that normally helps the immune system fight infections. In AAV, excessive activation of part of this system can amplify inflammation.
C5a, one of the proteins generated when complement is activated, contributes to blood vessel and tissue damage. The importance of this pathway is supported by the effectiveness of Tavneos (avacopan), an approved AAV therapy that blocks the C5a receptor.
Despite therapeutic advances, reliably monitoring AAV disease activity remains a major clinical challenge.
Recent evidence suggests that complement fragments are elevated in urine during active AAV. Because the kidneys are a major target of AAV, measuring these fragments in urine could offer a simpler way to assess kidney inflammation.
To test this hypothesis, researchers in Japan assessed whether urinary levels of three complement fragments — C3a, C5a, and C5b-9 — were associated with the severity of kidney damage, recovery of kidney function after treatment, and longer-term outcomes in people with AAV.
Study follows 57 patients with kidney involvement
The researchers retrospectively analyzed data from 57 patients (mean age 74; 63% women) treated for newly diagnosed or relapsing AAV at the University of Miyazaki Hospital, Japan, between 2019 and 2025. Most (88%) had microscopic polyangiitis (MPA), the most common type of AAV, and 97% tested positive for ANCAs against the myeloperoxidase (MPO) protein. All had evidence of kidney involvement, while some also had lung or neurological complications.
Urine samples were collected around the time of kidney biopsy or treatment initiation. However, 16 patients had already received glucocorticoids before their urine samples were collected, which the researchers noted could have affected urinary complement levels.
Treatment varied, with most patients receiving glucocorticoids, rituximab, or Tavneos. Patients were assessed at one, three, and six months after induction, with additional follow-up thereafter.
Levels of C3a, C5a, and C5b-9 were adjusted based on urinary creatinine levels to account for differences in how concentrated or diluted each urine sample was. Patients were divided into higher- and lower-level groups for each complement measure based on the median urinary level.
The study’s main outcome was a combination of death from any cause or progression to end-stage kidney disease (ESKD) requiring permanent dialysis. Secondary analyses examined changes in estimated glomerular filtration rate (eGFR), a measure of kidney function, and MPO-ANCA levels over time.
Over a median follow-up of 21.5 months, 14 patients reached the study’s main outcome of ESKD requiring chronic dialysis or death from any cause.
For each of the three complement markers — C3a, C5a, and C5b-9 — patients with high urinary levels had significantly poorer event-free survival than those with lower levels.
Higher urinary complement linked to poorer outcomes
In unadjusted analyses, people with high urinary C3a levels had a 3.86-fold higher risk of reaching the combined outcome of ESKD or death, while high C5a levels were linked to a 3.73-fold higher risk. High C5b-9 was also linked to a roughly threefold higher risk, but that finding was not statistically significant.
Additional analyses suggested that these associations were driven mainly by kidney-related outcomes, particularly progression to ESKD, rather than by deaths. The researchers cautioned that this analysis was limited by the small number of events.
C5a, however, stood out for being more consistently associated with other indicators of kidney disease severity.
Specifically, patients with lower urinary C5a showed significantly greater improvement in eGFR at one and three months after treatment.
Kidney biopsies were available from 47 patients. In an exploratory analysis, compared with those with low urinary C5a, patients with high levels of C5a had a greater proportion of cellular crescents — lesions that form in the kidney’s filtering units during severe inflammation.
They also had fewer normal glomeruli, the tiny structures in the kidney responsible for filtering blood, and greater involvement of the tubulointerstitial tissue surrounding the kidney tubules.
The researchers also explored whether combining urinary complement levels with initial eGFR could better distinguish kidney-related risk. Patients with both high complement levels and severely reduced kidney function had the poorest event-free survival, with the clearest separation seen when urinary C5a and eGFR were used together.
Overall, “urinary C5a is associated with renal outcomes, histopathological severity, and recovery of kidney function in ANCA-associated vasculitis,” the researchers wrote.
According to the team, larger prospective studies with repeated urinary measurements are necessary to determine whether C5a can reliably help predict treatment response, kidney recovery, relapse, or progression to ESKD. The researchers also noted that the small, single-center study included mainly older Japanese patients with MPO-ANCA-positive MPA, which may limit how broadly the findings apply.
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