Serum Tests Reveal Severity of IgA Nephropathy

/kidneynews/4_9/1/graphic/1f1.jpg

Findings from a new study could lead to better diagnosis and treatment of patients with immunoglobulin A (IgA) nephropathy, one of the most common diseases of the kidney. The results, published in the Journal of the American Society of Nephrology, indicate that increasing blood levels of certain autoantigens and autoantibodies may act as warning signs that a patient’s disease is worsening and that aggressive interventions are needed.

The findings also support a predominant role of an autoimmune mechanism in the pathogenesis of IgA nephropathy, which remains partly unsolved.

“The intimate details of the cascade of events leading eventually to destruction of the kidneys are complex and still puzzling,” said first author Francois Berthoux, MD, of the University Hospital of Saint-Etienne, in France.

Assessing disease severity

Patients with IgA nephropathy, a condition that was first described in 1968, have increased serum levels of IgA1 that is galactose deficient. In the absence of galactose, terminal N-acetylgalactosamine residues are exposed. Consequently, such IgA1 molecules are presented as autoantigens, and IgG or IgA glycan-specific autoantibodies recognize them to form immune complexes that circulate in the blood and can settle in the kidneys. These events can damage the kidneys, which subsequently leak blood and protein in the urine. IgA nephropathy can lead to high blood pressure, swelling, and, in some cases, kidney failure.

At the time of diagnosis, it remains difficult to predict the long-term clinical outcome for patients with IgA nephropathy. “The disease is clinically heterogeneous, with 20 percent to 30 percent of patients progressing to chronic kidney disease,” said Ian Roberts, MD, of the department of cellular pathology at John Radcliffe Hospital, in England, “The challenge is to identify those patients who will progress and could potentially benefit from immunosuppressive therapy.” Currently, assessment of disease severity is based partly on clinical and biochemical markers, such as proteinuria and the rate of loss of renal function, and partly on histologic features in kidney biopsy specimens, he said.

Better blood markers

To look for blood markers that might provide a better assessment of disease severity, Berthoux, along with Jan Novak, MD, PhD, of the University of Alabama at Birmingham; Hitoshi Suzuki, MD, PhD, of Juntendo University, in Tokyo, Japan; and their colleagues studied blood samples from 97 patients with IgA nephropathy and compared them with samples from 60 individuals without the disease (30 healthy individuals and 30 with non-IgA nephropathy disease).

In patients with IgA nephropathy, the analyses were performed on serum samples taken at the time of diagnostic biopsy. The average observation interval from the onset of clinical disease to the final event (dialysis or death) or last follow-up visit was 13.8 years, and from diagnosis by biopsy to final event or last follow-up visit, the interval was 7.3 years.

Mean serum levels of total autoantigen (U/mL), normalized IgG autoantibody (OD/0.5 µg), and total IgA autoantibody (U/mL) were significantly higher in patients than in the combined control individuals. Blood levels of both IgA1 autoantigen and the IgG and IgA antibodies increased in a stepwise fashion according to the severity of patients’ disease. Also, patients with high blood levels of antibodies against IgA1 at the time of diagnosis had a higher risk of eventually needing dialysis and dying prematurely. When the alternative definition for progressive IgA nephropathy based on reduced estimated GFR was used, only the normalized IgG autoantibody discriminated the progressors from the nonprogressors. In addition, there was no correlation between sex or age at diagnosis or sampling and any of the serum biomarkers.

“This paper is a first step, and in the future we have to refine these tests to check the impact of different treatments on these serum biomarkers, and to imagine new therapies with direct impacts on IgA1 or on the specific antibody responses against it,” said Berthoux. He and his coauthors wrote that their findings are “consistent with a multihit hypothesis for the disease mechanism of IgA nephropathy, wherein an increased serum level of autoantigen alone is not sufficient to induce renal injury; it must combine with autoantibodies either in the circulation to form immune complexes that deposit in the glomerular mesangium or in situ with galactose-deficient IgA1 already in the mesangium.”

The report offers a new risk factor that, if confirmed in additional studies, can serve as a marker for selecting patients to be aggressively treated.

“The international community of pathologists and nephrologists who worked on the Oxford classification of IgA nephropathy is highly interested in finding serologic markers that could be added on the pathology score. These efforts will hopefully provide a clue for selecting IgA nephropathy patients to be treated or not and to modulate the intensity of treatment in the likely progressors,” said Rosanna Coppo, MD, who was not involved with the study and is the director of the nephrology, dialysis and transplantation unit at Regina Margherita Children’s University Hospital in Turin, Italy. Her own work indicates that the nephrotoxicity of aberrantly glycosylated IgA1 in IgA nephropathy is enhanced in the presence of systemic signs of oxidative stress.

John Radcliffe Hospital’s Roberts, who also did not participate in the study, noted that the findings raise some important questions.

“It is unclear how the autoantibody levels change over time, and it remains to be ascertained whether levels correlate with clinical markers of activity in a longitudinal study. Another important area of future investigation is the link between autoantibody levels and histological activity in IgA nephropathy,” he said.

Notes

[1] Study coauthors include Lise Thibaudin, MD, Nicolas Maillard, MD, PhD, Christophe Mariat, MD, PhD (University Hospital of Saint-Etienne, France); Hiroyuki Yanagawa MD, PhD; Yasuhiko Tomino, MD, PhD (Juntendo University, Tokyo, Japan); and Bruce Julian, MD, PhD (University of Alabama at Birmingham).

[2] Disclosures: The authors reported no financial disclosures.

[3] The article, entitled “Serum autoantibodies specific for galactose-deficient IgA1 associate with disease progression in IgA nephropathy,” is available online at http://jasn.asnjournals.org/; doi:10.1681/ASN.2012010053.

September 2012 (Vol. 4, Number 9)