Persistent high urine protein levels sign of kidney failure, death risk

Study into 571 patients, most with GPA, who took part in five trials in Europe

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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ANCA-associated vasculitis (AAV) patients with proteinuria, elevated protein levels in their urine, after induction treatment are at a three times higher risk of kidney failure and/or death, according to a study based on data from five clinical trials.

Data also linked persistent hematuria, or blood in the urine, after such treatment to an increased risk of kidney disease.

“These parameters must be considered to assess long-term kidney prognosis of patients with AAV,” the researchers wrote.

The study, “Proteinuria and hematuria after remission induction are associated with outcome in ANCA-associated vasculitis,” was published in Kidney International.

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Protein and blood levels in urine tied to patient outcomes over time

A rare disease, AAV occurs when the immune system produces self-reactive antibodies that attack healthy immune cells, damaging small blood vessels in the body, including those in the kidneys.

When diagnosing AAV, doctors typically collect a urine sample to check if the kidneys are involved.

During the process of removing waste from blood, tiny filters in the kidneys prevent most proteins from being taken out of the body. If there is a problem with the kidneys, proteins can leak into urine and be excreted. A large amount of protein or blood in urine can be a sign kidney involvement.

Patients are usually treated with immunosuppressive medications to push the disease into remission, called induction treatment. After treatment, doctors can monitor kidney health by checking for continuing proteinuria and hematuria.

A group of researchers in Europe looked at data from five European AAV clinical trials to determine if persistent hematuria and proteinuria after induction treatment are indicators of a risk of kidney failure, mortality, or kidney relapse.

“At AAV diagnosis, hematuria and proteinuria are considered as biomarkers reflecting renal involvement. Yet, the prognostic value of their persistence after induction of remission … remains uncertain, although it could reflect either renal damage or persistent active disease,” the scientists wrote.

The Phase 3 MAINRITSAN (NCT00748644) and MAINRITSAN 2 (NCT01731561) trials were coordinated by the French Vasculitis Study Group, while the RITUXVAS (ISRCTN2852881), MYCYC (NCT00414128), and IMPROVE (NCT00307645) studies were under the European Vasculitis Society Network.

These trials started at different times between 2003 and 2016. All included people with either newly diagnosed or with relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis — the two most common types of AVV — and compared different immunosuppressive therapy schemes.

A total of 571 adult patients (336 men and 235 women) were included in this study. Their median age was 60, and the majority (67.6%) had GPA. More than half (59.8%) tested positive for antibodies against proteinase 3, and 34.8% tested positive for antibodies against myeloperoxidase. These are the main types of AAV-causing antibodies.

At the start of induction treatment, 77.2% of patients had kidney involvement. The most commonly used induction treatment was cyclophosphamide (75.2% of patients), followed by rituximab (14.7%), and mycophenolate mofetil (10%). After remission was achieved, patients were started on maintenance treatment.

Tests to measure patients’ urinary protein and blood levels at four to six months after induction treatment found persistent proteinuria in 165 of 481 patients (34.3%), and persistent hematuria in 157 of 526 (29.8%).

After a median follow-up of nearly 2.5 years, 42 patients (7.4%) experienced a kidney disease relapse, 16 (2.8%) developed kidney failure, and 13 (2.3%) died. The median time from the end of induction treatment to relapse, kidney failure, or death was nearly 2.5 years.

After adjusting for potential influencing factors such as age, antibody type, and maintenance therapy, persistent proteinuria after induction treatment was linked to a three times higher risk of death or kidney failure, the researchers reported.

Urine tests may be good way to manage kidney inflammation in AAV patients

Both persistent proteinuria and persistent hematuria were independent risk factors of kidney relapse, each increasing the risk by about two times. In addition, maintenance therapy with medications other than rituximab was linked to a sevenfold higher risk of relapse.

Similar results were obtained when looking only at data from patients with kidney involvement at the start of induction treatment.

“This study is, to our knowledge, the largest one to investigate the prognostic value of persistence of proteinuria and hematuria after the induction of remission in this disease,” the researchers wrote.

“Persistent proteinuria after induction therapy was associated with death/kidney failure and kidney relapse, whereas persistent hematuria was an independent predictor of kidney relapse,” they added.

While new disease biomarkers awaited “simple, non-invasive and costless assessment of proteinuria and hematuria should be used” to manage kidney inflammation in AAV, “especially to assess long-term [kidney] prognosis of these patients,” the team wrote.

The researchers noted that their results may not be generalized to all AAV patients, since those enrolled in these trials were “mostly of European ancestry, and only a minority of them received rituximab,” which “is now considered as standard-of-care therapy in AAV.”