Immune system gene activity linked to kidney damage in AAV study
Researchers urge further studies on complement-based therapy choices
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Elevated activity of genes of the complement pathway, a part of the immune system, in kidney tissue is associated with impaired kidney function and inflammation in adults with ANCA-associated vasculitis (AAV) and related kidney disease, a study shows.
Despite these findings, results from blood tests or tissue staining analysis only weakly reflected the observed complement gene activity in kidney tissue.
Researchers are calling for further studies to determine whether complement-based classification can inform therapeutic decisions or clinical trials and ultimately improve outcomes in AAV patients with kidney disease.
The study, “Multimodal profiling of complement expression and association with outcomes in ANCA-associated vasculitis with glomerulonephritis,” was published in Kidney International Reports.
Inflammation in AAV can damage kidney’s filtering units
In AAV, self-targeting antibodies, called ANCAs, drive inflammation and damage to small blood vessels. This can lead to glomerulonephritis, a condition marked by damage to the kidney’s filtering units (glomeruli), which can rapidly progress to kidney failure.
Emerging evidence suggests that the complement system, a set of proteins that normally helps the immune system fight infections, may amplify ANCA-driven inflammation. Complement proteins are usually inactive but become activated by foreign organisms or antibodies bound to them.
Whether complement activity in the kidney affects AAV patient outcomes and relates to blood test or biopsy results remains unclear. Biopsy refers to the collection of small tissue samples for analysis under a microscope.
In this study, a team led by researchers in France retrospectively analyzed complement system activity in 369 adults (60% men) with AAV-associated glomerulonephritis (AAV-GN). In terms of the AAV types, most cases (69%) had microscopic polyangiitis, while the rest had granulomatosis with polyangiitis.
Low blood levels of C3 protein associated with kidney failure, death
Over a median follow-up of 60 months (five years), 17% of patients experienced kidney disease relapse, 29% progressed to kidney failure, and 31% died.
Complement activity was assessed in three ways: blood levels of two complement proteins, C3 and C4; staining for C1q and C3 protein deposits in kidney biopsy tissue; and gene activity of complement-related genes in kidney tissue.
Blood tests found that below-normal levels of C3 and C4 were uncommon, occurring in 3.4% of AAV-GN patients for each protein. Even so, low blood levels of C3, but not C4, were independently associated with kidney failure and death.
Researchers detected C1q deposits in 11% of kidney biopsy samples, while C3 deposits were found in around half (47%). C1q deposition was independently associated with kidney failure and death, and C3 deposition was independently tied to an increased risk of death.
In addition, kidneys from AAV-GN patients showed increased activity of several complement-related genes compared with samples from healthy individuals. The overactive genes included C1QA, C1QB, C2, C3, C5AR1, CFB, CFD, and CFH.
Gene activity scores higher in AAV-GN kidneys
Based on these results, the team created two gene activity scores: one for the activity of the classical complement pathway, which is dependent on antibodies, and one for alternative pathway activity, which is activated independently of antibodies.
Both scores were significantly higher in AAV-GN kidneys than in healthy controls and correlated with kidney function, urine protein levels (a marker of kidney damage) and C-reactive protein (a marker of inflammation), and biospy features. Still, the scores didn’t correlate with disease activity.
Notably, these kidney gene activity scores showed no meaningful association to blood C3 or C4 levels or C1q or C3 deposition results, indicating that blood tests, biopsy results, and gene activity readouts “capture partially distinct dimensions of complement biology in AAV-GN,” the team wrote.
In contrast, the gene activity scores strongly correlated with markers of immune cells in the tissue, “indicating that bulk complement-related [gene activity] is closely linked to the inflammatory cellular architecture of AAV-GN lesions,” the researchers wrote.
Regarding outcomes, high classical pathway scores were tied to more severe kidney disease at diagnosis, including poorer kidney function, fewer normal glomeruli, and more severe inflammation. After adjusting for potential influencing factors, statistical analyses showed that this score was not independently linked to kidney failure, relapse, or death.
[Studies following patients over time] will be needed to determine whether complement-based stratification can inform trial enrichment or therapeutic decisions and ultimately improve outcomes in AAV-GN.
Likewise, higher alternative pathway score was associated with more severe kidney disease at presentation. Adjusted statistical analyses demonstrated that low alternative pathway scores were independently associated with a lower likelihood of kidney failure and death.
To confirm these findings, the researchers used two publicly available data sets that mapped gene activity to specific locations and cell types within kidney tissue. Data showed that both classical and alternative pathway scores were increased in AAV-GN kidneys, and the increase was found in both inflamed and noninflamed areas.
In addition, classical pathway gene activity was concentrated mainly in immune cells, while C3 gene activity was found in both immune and nonimmune cells.
In a final analysis, the combined results across all three gene activity datasets found that several genes (C1QB, C1QC, C3, CFB, and CFH) showed consistent and substantial differences between AAV-GN and control kidneys across all platforms.
“The reproducibility of [kidney] complement-related [activity] across independent [gene activity] platforms [,] and its association with clinical outcomes, support the relevance of tissue-level complement profiling alongside circulating biomarkers and routine [tissue staining] in AAV-GN,” the team wrote. Studies following patients over time “will be needed to determine whether complement-based stratification can inform trial enrichment or therapeutic decisions and ultimately improve outcomes in AAV-GN.”
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