Urinary biomarkers match kidney biopsies, predict outcomes

Urine samples were collected from 45 AAV patients with confirmed kidney involvement

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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An image of a person drinking from a glass and a view from behind shows his kidneys at work.

Urine levels of scarring, inflammation, and kidney damage biomarkers accurately reflect kidney biopsy results and predict kidney outcomes in people with ANCA-associated vasculitis (AAV), a pilot study suggests.

According to its researchers, noninvasive urine tests could be used to monitor tissue or functional changes in the kidneys. Also, urinary biomarkers may replace invasive biopsies to assess kidney health in the future.

The study, “Biomarkers of fibrosis, kidney tissue injury and inflammation may predict severity and outcome of renal ANCA – associated vasculitis,” was published in Frontiers in Immunology.

In AAV, self-reactive antibodies, called ANCAs, mistakenly bind certain enzymes in neutrophils, a type of immune cell, activating them and causing inflammation and damage to small blood vessels.

In about 70% of cases, glomeruli, the kidney’s filtration units that contain tiny blood vessels, become inflamed — a condition called glomerulonephritis, which can affect normal kidney function and possibly lead to kidney failure.

A kidney biopsy, wherein a small piece of tissue is collected and examined under a microscope, is a standard test to confirm an AAV diagnosis and assess disease activity or progression.

The procedure is invasive and often involves being admitted to the hospital as an inpatient, however. Some patients, however, may not be eligible for one, due to disease severity.

“Urinary biomarkers able to assess the type, extent and, potentially, prognosis [outcomes] of kidney disease in AAV are needed,” wrote a team of researchers in Czechia who assessed whether a panel of urinary biomarkers for fibrosis (scarring), kidney tissue injury, and inflammation could determine the severity of kidney involvement and predict kidney outcomes in AAV.

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Comparing biopsy results, urinary biomarkers

They collected urine samples from 45 AAV patients with confirmed kidney involvement at the time of biopsy and compared the biopsy results with those of urinary biomarkers. These included DKK-3, a marker of kidney tissue damage and fibrosis; the kidney fibrosis marker PRO-C6; CD163, a biomarker of kidney inflammation; and EGF and C3M, lower levels of which indicate worse kidney tissue damage or fibrosis.

“To our knowledge, this is the first time these biomarkers have been studied together in a cohort of AAV patients,” the researchers wrote.

Initial tests showed urinary levels of DKK-3, PRO-C6, and CD163 were significantly higher and EGF and C3M levels were significantly lower in patients than in 10 healthy people who served as controls.

Biopsy results were reported as four classes — focal, crescentic, sclerotic, and mixed. In the focal class, more than 50% of glomeruli are normal and in crescentic, more than 50% have cellular crescents, a hallmark of glomerulonephritis. The sclerotic class is defined as more than 50% globally sclerotic (scarred) glomeruli and the mixed class meets none of these criteria.

Urinary DKK-3 and PRO-C6 levels were the highest in patients with sclerotic kidney damage and lowest in the focal biopsy group. In turn, the highest urinary CD163 levels were found in the crescentic group and the highest EGF and C3M levels were found with focal kidney damage.

Combined results from all five biomarkers were able to distinguish the focal class from the others with 90% accuracy. When blood levels of creatinine, a standard kidney function marker, were included in the model, the accuracy increased to 92.5%.

Biomarker levels could also discriminate focal from crescentic classes with 95.2% accuracy and focal from sclerotic classes with 95.4% accuracy. These models reached up to 100% accuracy when biomarker levels were combined with those of creatinine.

By contrast, combined urinary biomarker tests reached an accuracy of 63.2% at discriminating between crescentic and sclerotic classes, and 73.7% accuracy with creatinine.

Urinary DKK-3 and PRO-C6 levels were highest in those with more than 25% kidney fibrosis, while EGF and C3M levels were highest in patients with less than 25% fibrosis. C3M results didn’t reach statistical significance, however.

Sclerotic and mixed biopsy classes were mainly found in patients who tested positive for ANCAs targeting the MPO enzyme, while those with ANCAs against PR3 “were represented mostly in the focal biopsy class,” the researchers wrote. No significant differences were found in urinary biomarker levels between patients with anti-MPO ANCAs and those with anti-PR3 ANCAs.

Kidney outcomes

During a median follow-up of 38 months, about three years, and ranging from one to six years, eight patients (18%) reached kidney failure.

The combined levels of the urinary biomarker panel at the diagnosis distinguished patients who eventually saw a favorable kidney outcome from those with an unfavorable outcome “with 88.9% accuracy, or 92.6% accuracy with [blood] creatinine included,” the researchers wrote.

Urinary DKK-3 and PRO-C6 levels, collected at the biopsy, were significantly higher in patients who eventually had worse kidney function by the end of follow-up. In contrast, better kidney outcomes occurred with significantly higher urinary EGF and C3M levels at biopsy.

“This small study demonstrated that noninvasive biomarkers of fibrosis, inflammation, and kidney tissue injury were associated with severity of [kidney] involvement and prognosis of kidney disease progression in patients with AAV,” the researchers wrote, adding larger studies are needed to confirm the findings and monitor changes in these biomarkers over time.