Second protein associated with common cause of kidney failure identified

An international team of researchers including Jon Klein, M.D., Ph.D., and Michael Merchant, Ph.D., of the University of Louisville (UofL) has identified a protein that turns a person's immune system against itself in a form of kidney disease called membranous nephropathy (MN). The findings are published online in the New England Journal of Medicine.

This is the second protein associated with MN and the development of an autoimmune response.

Through the identification of this second protein, a new blood test can be developed to diagnose this common form of kidney disease.

Unchecked, MN can lead to kidney failure, or end stage renal disease. In 2011, more than a million people worldwide suffered from kidney failure annually, with more than 570,000 in the United States. Approximately 14 per cent of those cases are the result of glomerulonephritis of which MN is a common cause.

''Five years ago this team initially discovered a protein that has led to a blood test identifying between 70 and 80 per cent of people with MN,'' said Klein, vice dean of research at UofL's School of Medicine. ''We now have found another protein that impacts up to another 5 per cent of patients with MN. Once a blood test is available, we will have been able to reduce the number of kidney biopsies necessary for disease detection and to assess the response to treatment by up to 85 percent.''

Membranous nephropathy occurs when the small blood vessels in the kidney that filter wastes from the blood become inflamed and thickened. As a result, proteins leak from the damaged blood vessels into the urine. For many people, loss of these proteins eventually causes signs and symptoms known as nephrotic syndrome.

In 2009, Klein and this team reported the discovery that antibodies to kidney expression of phospholipase A2 receptor 1 (PLA2R1), were diagnostic for MN. That work, also reported in the New England Journal of Medicine, led to an FDA-approved test to diagnose MN. The PLA2R1 antibody test is positive in 80 per cent of patients with MN. This week's disclosure is related to the protein THSD7A. Researchers examined the blood of people known to have MN. Of the 154 people studied, 15 had antibodies to THSD7A, but not PLA2R1.

''This is significant because it provides us with another marker of identification and enables us to lessen the physical burden on our patients and ultimately will decrease the need for kidney biopsy. These MN antibody tests also allow us to monitor disease activity without kidney biopsy as we treat the patient. This allows a more rapid approach to developing new therapies for MN,'' Klein said.

As pointed out by senior author Gérard Lambeau, Ph.D., director of research at Centre National de la Recherche Scientifique and Université de Nice Sophia Antipolis, Valbonne and team leader at the Institute of Molecular and Cellular Pharmacology (Sophia Antipolis), ''This week's disclosure is related to the discovery of the protein THSD7A and the corresponding anti-THSD7A autoantibodies in a group of about 10 percent of MN patients who did not have anti-PLA2R1 autoantibodies.''

''The discovery of this second antigen-antibody system in membranous nephropathy will allow clinicians to diagnose this new form of primary (autoimmune) membranous nephropathy and provides a new method to monitor the disease activity in this subgroup of patients,'' said co-lead authors Nicola Tomas, M.D. of University Medical Center Hamburg–Eppendorf and Laurence Beck, M.D., Ph.D., of Boston University School of Medicine.

Catherine Meyer-Schwesinger, M.D., Barbara Seitz-Polski, M.D., Hong Ma, Ph.D., Gunther Zahner, Ph.D., Guillaume Dolla, M.S., Elion Hoxha, M.D., Udo Helmchen, M.D., Anne-Sophie Dabert-Gay, Ph.D., Delphine Debayle, Ph.D., David J. Salant, M.D., and Rolf A.K. Stahl, M.D., are part of the research team.

In addition to the online version of the New England Journal of Medicine, the findings recently were presented at the American Society of Nephrology Kidney Week 2014 in Philadelphia.