Complement protein in blood may predict kidney damage in MPA
Researchers set a baseline cutoff level for C4, creatinine as part of study
High blood levels of the immune protein C4 are significantly associated with greater kidney-specific disease activity and a higher chance of developing kidney failure with microscopic polyangiitis (MPA), the most common type of ANCA-associated vasculitis (AAV), a study shows.
For this reason, measuring blood C4 levels may help predict the risk of kidney failure in this patient subgroup, the researchers said in “Serum Complement C4 Levels Are a Useful Biomarker for Predicting End-Stage Renal Disease in Microscopic Polyangiitis,” which was published in the International Journal of Molecular Sciences.
AAV is a group of conditions marked by abnormal immune responses that cause inflammation and damage to small blood vessels. ANCAs are a type of self-reactive antibody involved in AAV’s autoimmune attacks.
“MPA is a type of AAV that primarily affects the lungs and kidneys,” the researchers wrote, adding that nearly 80% of MPA patients have kidney involvement, which can progress into end-stage renal disease (ESRD), or kidney failure, despite treatment.
Risk factors in MPA
While several risk factors of kidney failure with AAV have been identified and were used to develop scoring systems to predict such outcomes, risk factors in MPA “have not been fully elucidated,” wrote researchers at Osaka Medical and Pharmaceutical University, Japan, who reviewed data from 74 people with MPA seen at their clinic between 2010 and 2021.
Half the patients were women, the median age was 75 (range, 70-79), and all except one were positive for ANCAs targeting myeloperoxidase (MPO), the type of self-reactive antibody most commonly found with MPA. During follow-up, 12 of these patients (16.2%) developed kidney failure.
Using blood samples collected at baseline — at the time of diagnosis and before remission induction treatment — the researchers conducted statistical tests that looked for markers that were significantly altered in those who later developed kidney failure.
Since the over-activation of the immune system’s complement cascade is thought to contribute to AAV, the researchers also looked for the levels of two of its proteins, C3 and C4.
Higher C4 levels with kidney failure
Those who developed kidney failure had significantly higher C4 levels, but significantly lower levels of C3, at the study’s start. This subgroup also had significantly higher initial levels of creatinine, a well-established marker of kidney dysfunction, and tended to have more severe AAV kidney disease, as measured by the Birmingham vasculitis activity score (BVAS).
Higher blood C4 levels were independently and significantly associated with a 24% higher likelihood of kidney failure, statistical analyses indicated, while higher creatinine levels were linked to a four times higher chance of it.
“In this study, we first revealed that high serum [blood] C4 levels are associated with the progression of ESRD and correlate with [kidney] disease severity in MPA,” the researchers wrote.
In further statistical tests, the researchers calculated the best cutoff values of C4 and creatinine to predict the risk of kidney failure. These were 29.6 milligrams per decaliter of blood (mg/dL) for C4 and 3.54 mg/dL for creatinine.
All eight patients who had C4 and creatinine levels higher than the cutoffs developed ESRD within two years of being diagnosed with MPA.
More than half (60.5%) of patients with only one or the other of the markers above the cutoff and nearly all (96.2%) of those with neither were free of ESRD after five years of follow-up.
Higher blood C4 levels also were significantly associated with higher blood creatinine levels and higher kidney BVAS scores, indicating more severe kidney disease.
Combined with studies that have shown similar results, the data suggest blood C4 levels “were a predictive biomarker for evaluating [kidney] disease severity in MPA,” the researchers wrote. “Our study showed that the optimal cutoff of baseline serum C4 levels for ESRD progression was set at 29.6 mg/dL, and measuring whether baseline serum C4 level is over this cutoff level may be an invasive and useful method for predicting ESRD in MPA.”
The study was limited by its retrospective nature, its small size, and the fact that all the patients were Japanese and had MPA, meaning it’s not certain if the findings may apply to other populations and AAV types, noted the researchers, who said more research was needed into the potential for C4 to be a marker of kidney disease in AAV. More research was also needed to better understand the biological role of this complement protein in the disease, they said.