The Membranous Nephropathy Trial of Rituximab (MENTOR) study is poised to change first-line-treatment recommendations for idiopathic membranous nephropathy.
Daniel C. Cattran, FRCP(C), MD, senior scientist at Toronto General Research Institute, part of the University Health Network based in Toronto, is leading the study along with recent Renal & Urology News “Expert Q&A” interviewee Fernando C. Fervenza, MD, PhD. Dr. Cattran explains why MENTOR may yield significant findings.
How prevalent is membranous nephropathy?
Dr. Cattran: Membranous nephropathy remains the most common cause of adult-onset nephrotic syndrome. However, it still fulfills the definition of an orphan disease, with an annual incidence of less than 5/100,000 population.
Which nephrology patients are most at risk for this condition?
Dr. Cattran: Although membranous nephropathy can occur at any age, it does have its peak incidence now in patients in their early 50’s. The age of presentation of the disease has gradually increased from the early 30’s in the 1980’s to the mid-40’s in the 1990’s, and now the 50’s. Males are affected twice as often as females and tend to have more severe disease at onset. Idiopathic membranous nephropathy rarely affects children.
Your study will focus on idiopathic membranous nephropathy. Is this a difficult diagnosis to make?
Dr. Cattran: Because idiopathic membranous nephropathy means that no specific cause of the process can be determined, it is therefore considered to be a diagnosis of exclusion—i.e., you must rule out secondary causes. Since many of the known causes for the membranous pattern of injury have completely different approaches to treatment, it is essential that the practitioner make the correct diagnosis.
Although the histologic diagnosis of membranous nephropathy can be made on kidney biopsy tissue alone, ruling out secondary causes requires additional thorough investigation. Some of the known secondary causes are systemic lupus erythematosus, certain drugs, and, perhaps most worrisome, malignancies.
How can nephrologists recognize this condition?
Dr. Cattran: The great majority of patients present with the clinical features of the nephrotic syndrome, including edema, proteinuria, hypoalbuminemia, and hyperlipidemia. About 25% of patients present with only proteinuria and are otherwise asymptomatic. This proteinuria is often found on routine examinations of the urine done by the patient’s family doctor or for insurance purposes.
The actual diagnosis of membranous nephropathy, a specific pattern of tissue injury, can only be made on examination of the renal tissue through biopsy.
Can nephrologists avert or minimize membranous nephropathy in these patients?
Dr. Cattran: At this point there is no way to avert the condition. The natural history of the idiopathic form of MGN—membranous glomerulonephritis, which is another name for membranous nephropathy—is quite distinct.
Approximately one third of patients will have a spontaneous remission, most of these occurring within the first two years after presentation. Another third of patients will have persistent low-grade proteinuria but long-term preservation of glomerular filtration function—that is, normal serum creatinine.
The remaining third tends to have a higher grade of proteinuria than the other two groups and can have either slow, or rarely rapid, progression to renal failure over the course of years.
What might your study reveal about thickening of the glomerular basement membrane—the cause of membranous nephropathy?
Dr. Cattran: It has long been recognized that the thickening of the glomerular basement membrane (GBM) is a reaction to the injury of presumed antigen-antibody complexes depositing on the subepithelial surface of the GBM.
In the last few years, several autoantibodies have been found in humans with membranous nephropathy. The most important one, which was discovered in 2009, is an autoantibody to the phospholipase A2 receptor antigen. It has subsequently been found to be located in the glomerular epithelial cell, i.e., the podocyte. This antigen/antibody complex stimulates the formation of new basement membrane tissue that grows up and around the antigen-antibody complex deposits and creates thickening of the GBM when viewed down the microscope.
There is increasing evidence that the autoantibody titer in the serum can be used to help monitor and perhaps even guide when and what to use in therapy of these MGN cases, and this is part of the monitoring that we will be doing in this study. However, much of this information is still quite preliminary, and there is still a lot of work to do.