Second protein associated with common cause of kidney failure identified.


An international team of researchers led by the University of Louisville 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 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 percent 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 percent of people with MN. The team have found another protein that impacts up to another 5 percent of patients with MN. Once a blood test is available, the results of this study 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 the 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 percent of patients with MN. The current study 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.

The group state that this is significant because it provides another marker of identification and enables the medical community to lessen the physical burden on patients and ultimately will decrease the need for kidney biopsy. These MN antibody tests also allow the medical team to monitor disease activity without kidney biopsy as they treat the patient. This allows a more rapid approach to developing new therapies for MN.

This new finding 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 team state that 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.

Source:  University of Louisville

 

Identification of the Target Antigen.  Panel A shows reactivity of serum samples with human glomerular extracts (HGE) and recombinant thrombospondin type-1 domain-containing 7A (rTHSD7A). Only samples from patients with membranous nephropathy (MN) that previously recognized the 250-kD protein present in HGE also recognized rTHSD7A (MN 1, MN 2, and MN 3). Panel B shows results of immunoprecipitation experiments. All serum samples from patients with membranous nephropathy that previously recognized rTHSD7A precipitated the antigen from HGE. No immunoprecipitation occurred with serum from healthy controls or with no serum (i.e., with water substituted for serum in the experiment). IgG4 was efficiently immunoprecipitated in all conditions (lower panel). Panel C shows the molecular architecture of THSD7A, with a large extracellular region comprising 11 thrombospondin type-1 domains (TSDs), 14 glycosylation sites (N), and 1 predicted arginine–glycine–aspartic acid (RGD) motif. The scheme was built according to the UniProt accession number Q9UPZ6 for THSD7A and ScanProsite tool from ExPASy.  Thrombospondin Type-1 Domain-Containing 7A in Idiopathic Membranous Nephropathy.  Lambeau et al 2014.

Identification of the Target Antigen. Panel A shows reactivity of serum samples with human glomerular extracts (HGE) and recombinant thrombospondin type-1 domain-containing 7A (rTHSD7A). Only samples from patients with membranous nephropathy (MN) that previously recognized the 250-kD protein present in HGE also recognized rTHSD7A (MN 1, MN 2, and MN 3). Panel B shows results of immunoprecipitation experiments. All serum samples from patients with membranous nephropathy that previously recognized rTHSD7A precipitated the antigen from HGE. No immunoprecipitation occurred with serum from healthy controls or with no serum (i.e., with water substituted for serum in the experiment). IgG4 was efficiently immunoprecipitated in all conditions (lower panel). Panel C shows the molecular architecture of THSD7A, with a large extracellular region comprising 11 thrombospondin type-1 domains (TSDs), 14 glycosylation sites (N), and 1 predicted arginine–glycine–aspartic acid (RGD) motif. The scheme was built according to the UniProt accession number Q9UPZ6 for THSD7A and ScanProsite tool from ExPASy. Thrombospondin Type-1 Domain-Containing 7A in Idiopathic Membranous Nephropathy. Lambeau et al 2014.

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