The initiating event in many chronic and progressive kidney diseases is the breakdown of the kidney filtration barrier, leading to abnormal protein loss in the urine called proteinuria.
Decades ago, investigators speculated that disruption of calcium signaling might be one of the early events leading to kidney disease through damage of podocytes, specialized kidney cells that mediate an essential filtration barrier function. Podocyte injury is thought to be the predominant – and potentially reversible – mechanism in the nephrotic syndrome and related proteinuric kidney diseases.
There are currently few therapies to protect the kidney’s essential filtration barrier. However, groundbreaking work by Anna Greka, MD, PhD, and colleagues in her lab at Brigham and Women’s Hospital (BWH) have identified a small-molecule compound which in pre-clinical models has been shown to protect podocytes and preserve the kidney filter, thereby preventing or ameliorating proteinuric kidney disease.
Dr. Greka is the director of the new Center for Glomerular Kidney Disease and Novel Experimental Therapeutics (Glom-NExT) at BWH, which is dedicated to the discovery of personalized and targeted treatments to cure kidney disease.
As Dr. Greka and colleagues reported in the Journal of Clinical Investigation (2013;123(12):5298–5309), the calcium-permeable ion channel TRPC5 is a mediator of filtration barrier injury: when induced to become overactive, TRPC5 leads to damage of the actin cytoskeleton and podocyte injury.
The Greka laboratory also showed that blocking TRPC5 with the small molecule inhibitor ML204 rescues podocytes from cytoskeletal remodeling in vitro, thereby preserving podocyte function and maintaining the integrity of the kidney filtration barrier. Furthermore, they showed that the molecule protects against TRCP5-mediated podocyte injury in models of kidney disease.
“We were able to find a potential therapeutic importance for this small molecule inhibitor, by showing that it can be used for the targeted treatment of kidney disease,” Dr. Greka said. “For the past few decades there has been little progress in therapies for kidney disease, an area of tremendous unmet need.”
Dr. Greka added, “Much excitement at this time also comes from the fact that we are starting to develop podocyte-targeted treatments for patients.”
One of the other therapies in development for the treatment of patients with proteinuric kidney disease is abatacept, a drug currently on the market for treatment of rheumatoid arthritis. As Dr. Greka and Peter Mundel, MD, of Massachusetts General Hospital and colleagues reported in 2013 in The New England Journal of Medicine (369:2416-23), abatacept induced complete or partial remissions in patients with proteinuric kidney disease where biopsies showed podocyte expression of B7-1, also known as CD80. Successfully treated patients included four individuals with focal segmental glomerulosclerosis (FSGS) resistant to the CD20 inhibitor rituximab, and one with primary FSGS resistant to the glucocorticoid prednisone.
Normally, podocytes do not express B7-1, but detailed mechanistic work in Dr. Mundel’s laboratory had revealed B7-1 induction in many models of podocyte injury. Furthermore, immunostaining in randomly selected biopsy specimens from patients with proteinuric kidney diseases was positive for B7-1. These findings suggest that B7-1 is induced in the course of disease, and point to B7-1/CD80 as a possible biomarker for the targeted treatment of proteinuric kidney diseases.
Dr. Greka and colleagues are now planning for a multicenter randomized controlled clinical trial of the drug in patients with refractory nephrotic syndrome. For more information on enrolling a patient, contact Dr. Greka at agreka@partners.org.
In weekly clinics, Glom-NExT staff provide consultations and specialty care for patients with the most common proteinuric kidney diseases (such as diabetic and hypertensive kidney disease), in addition to those with more complex conditions such as focal segmental glomerulosclerosis (FSGS), minimal change disease, membranous nephropathy, IgA nephropathy, lupus and inflammatory glomerulonephritis and vasculitis.
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