Identifying Biomarkers in Nephrotic Syndrome: A Paradigm Shift in Medicine Toward Targeted Therapy

Author: Aaron Kirkemo, MD, senior global medical director

Medical science today is making strides to better understand disease at a molecular level in order to identify more targeted ways of treating patients. As understanding of the pathophysiology of diseases—why and how they occur—increases, we can help physicians better understand which of their patients might benefit from therapy and at what point during the course of their disease.

Biomarkers are playing an important role in this changing healthcare landscape. Biomarkers, or biological markers, are measurable indicators of biological states or conditions. For example, cholesterol levels are a commonly known biomarker that can be measured and used to assess an individual’s risk of cardiovascular disease. Biomarkers can also be used to determine how a disease will progress in an individual patient, allowing clinicians to offer more targeted interventions and treatments for patients geared to their specific disease course and treatment goals. This is the future of medicine, one in which treatments are highly tailored versus a one-size-fits-all approach.

Mallinckrodt is studying or supporting research of biomarkers in rare kidney disorders called nephrotic syndrome, diseases that impact approximately 35,000 people in the United States.1 Biomarkers hold great promise in rare diseases that affect small numbers of patients. Conducting clinical trials can be challenging when diseases affect only a few thousand patients, which is why research to identify biomarkers in rare diseases like nephrotic syndrome can help inform clinicians about how to optimally manage their patients with various degrees of disease manifestation.

In the kidney, there are specialized structures that filter the body’s blood. They are called glomeruli. The blood vessels in the glomeruli are covered by very specialized cells, called podocytes, that create small filtration pores to let water and small molecules pass into the urinary space, but hold back the protein and immunoglobulins in the blood. If the glomerulus is injured, these pores open up and the body begins to leak protein into the urine. This is called proteinuria. As the proteinuria increases, patients will gain large amounts of weight due to water retention. They also have problems with high blood pressure, elevated lipid levels and are at risk of heart attacks, strokes, blood clots, infections and other complications.2-5 In patients whose disease is not well controlled, the kidneys can fail, requiring dialysis or a kidney transplant 6

Scientists have discovered a biomarker present in roughly 70 percent of nephrotic syndrome cases due to idiopathic Membranous Nephropathy (iMN). It is an autoantibody to the M-type phospholipase A2 receptor (PLA2R) located on the podocytes. This autoantibody is called anti-PLA2R. Level of this antibody in the blood   correlates with disease activity and progression.7,8 A blood test for the PLA2R biomarker can be used as an indicator of therapeutic response and augment other testing to determine the best treatment approach for each patient. For example, evidence of aggressive disease might warrant treatment with immunosuppressive agents, whereas less aggressive disease could indicate a conservative treatment initially, preventing or limiting unnecessary treatment with immunosuppressive agents that suppress the body’s immune system and can have serious and toxic side effects.9

We are witnessing an exciting paradigm shift in medicine, one in which treatments and therapeutic approaches will more closely align with each patient’s unique biology and disease progression. Mallinckrodt supports this research being conducted globally to identify biomarkers that will be used as essential elements of clinical practice today and in the future.

1. Data on File, Mallinckrodt Pharmaceuticals

2 Johnson RJ, et al. Introduction to glomerular disease: histologic classification and pathogenesis. In: Floege J, Johnson RJ, Feehally J, eds. Comprehensive Clinical Nephrology. St. Louis, MO: Saunders; 2010:208-217.

3 Jefferson JA, et al. Am J Kidney Dis. 2011;58: 666-677.

4 Kriz W, et al. Renal anatomy. In: Floege J, et al, eds. Comprehensive Clinical Nephrology. St. Louis, MO: Elsevier Saunders; 2010:3-14.

5 Shirley DG, et al. Renal physiology. In: Floege J, et al, eds. Comprehensive Clinical Nephrology. St. Louis, MO: Elsevier Saunders; 2010:15-28.

6 Troyanov, Stéphan, Catherine A. Wall, James W. Scholey, Judith A. Miller, Daniel C. Cattran, and For The Toronto Glomerulonephritis Registry Group. “Idiopathic membranous nephropathy: definition and relevance of a partial remission.” Kidney international 66, no. 3 (2004): 1199-1205.

7 Schlumberger W, Hornig N, Lange S, et al: Differential diagnosis of membranous nephropathy with autoantibodies to phospholipase A2 receptor 1. Autoimmun Rev 2014 Feb;13(2)108-113

8 Beck Jr, Laurence H., Ramon GB Bonegio, Gérard Lambeau, David M. Beck, David W. Powell, Timothy D. Cummins, Jon B. Klein, and David J. Salant. “M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.” New England Journal of Medicine 361, no. 1 (2009): 11-21.

9 De Vriese, An S., Richard J. Glassock, Karl A. Nath, Sanjeev Sethi, and Fernando C. Fervenza. “A Proposal for a serology-based approach to membranous nephropathy.” Journal of the American Society of Nephrology 28, no. 2 (2017): 421-430.