Shedding New Light on a Rare Form of Proteinuric Kidney Disease
In 2022, Astrid Weins MD, PhD, the chief of integrated renal pathology at Mass General Brigham and an assistant professor of pathology at Harvard Medical School with her research team based in the BWH Division of Nephrology made a breakthrough discovery. They had found the likely cause for a proteinuric kidney disease known as “Minimal Change Disease" (MCD), historically named for the absence of visible light microscopic findings in kidney biopsies from patients suffering from this disorder.
Their discovery ended decades of speculation about the cause of this disease which had been an unsolved mystery in nephrology. Despite its seemingly benign name, patients suffering from MCD can experience severe and debilitating symptoms. These include edema, massive protein loss in the urine, a high lipid profile and low serum albumin, and some may advance to advanced kidney scarring and eventually require a kidney transplant. The identification of autoantibodies against nephrin, a major component of the kidney filter as the likely culprit, for the first time defined MCD as an autoimmune disease. This insight provided a rationale for B cell depletive treatment and research aimed at identifying new drug targets.
This spring, Weins joined an international team of collaborative researchers led by German podocyte researcher Professor Tobias Huber in publishing a New England Journal of Medicine paper, titled “Autoantibodies Targeting Nephrin in Podocytopathies,” which further advanced Weins’ prior research. The new study expanded her findings to large European cohorts of adult and pediatric nephrotic patients with MCD and so-called Primary Focal and Segmental Glomerulosclerosis (FSGS), and reproduced the disease in preclinical models, validating the original study and suggesting better treatment options for patients. Weins discusses her work, the new findings, and their implications for patients.
What is the focus of your research?
My research focus is proteinuric kidney disease, meaning we are working on mechanisms that lead to protein spilling into the urine. Most of those diseases affect a particular cell type in the kidney called podocyte; the name is derived from the fact that they extend processes or “feet” that form an organized interdigitating network which forms part of the kidney filter. A protein-based structure connecting those feet, called the slit diaphragm, is disrupted or not properly formed in patients with proteinuria.
What is known about the proteinuric kidney disease known as “Minimal Change Disease,” and how is it currently treated?
It’s a well-known disease seen at all ages but more commonly seen in children who can develop severe edema, often diagnosed following a viral infection. Children usually receive immediate empiric corticosteroid treatment, and most respond within few days. Adults with nephrotic syndrome usually undergo a kidney biopsy, and after diagnosis are treated with corticosteroids as well. Most patients respond well but some do not, and those who do respond may relapse frequently and may require additional immunosuppressive therapy. Patients with frequently relapsing or non-responding disease can develop kidney scarring, eventually needing dialysis and transplant. Unfortunately, the disease will recur in the transplanted kidney of about 50% of patients who receive a transplant, a complication that is very hard to treat and often leads to devastating transplant loss.
As pathologists, what have you seen from kidney biopsies?
Traditionally, biopsies of patients with MCD have been described as having no defining features by light and immunofluorescence microscopy, while by electron microscopy, a technique providing high resolution, the profound injury to the podocytes, and hence the glomerular filter, is recognized. However, looking carefully at the glomeruli, filtering units in the kidney, by immunofluorescence microscopy, we observed a very fine, subtle, granular ‘dusting’ for Immunoglobulin G (IgG), a major antibody type, over the podocytes. By using co-staining and high-resolution microscopy techniques, we determined this dusting was actually an autoantibody binding to a protein component of the kidney filter, named nephrin, which is relocalized and clustered by the antibody. Inspired by this observation in kidney biopsies, we were then able to identify the antibody in the circulation by developing a specific test to measure antibody levels in the patients’ blood.
What did the new study in the NEJM show?
Beyond a validation of our study in much larger and different patient cohorts, the recent study published in NEJM now provides the ultimate proof of causality by elegantly recapitulating the disease in a mouse model. Initially, we assisted the European group with setting up their assay, but eventually it became a truly independent and very important validation and expansion of our work. While the German researchers led by Tobias Huber, Felicitas Hengel and Nicola Tomas performed the bulk of the research, it turned into a fruitful collaborative effort involving many international teams unified by the International Society of Glomerular Disease.
What does this mean for patients with kidney disease?
We found that up to 70% of patients diagnosed with MCD and in around 25% with Primary FSGS had antibodies against nephrin. In children with Idiopathic Nephrotic Syndrome (INS), the antibody is even found in up to 90% of patients. Based on these findings, we can now explain to our patients why the disease occurs and why corticosteroids and immunosuppressive treatments are likely to work. The development of a specific blood test will enable us to follow antibody levels in the blood and potentially determine treatment success and predict recurrences.
Understanding a disease is equally important to patients and to clinicians treating them. It is really a paradigm shift in how we view this disease and how we communicate with and treat our patients. Moreover, it gives us the ability to target the production of antibodies in B cells, and maybe by even more specific therapies that may limit side effects.
Do those medications exist?
A: Not yet. However, we can learn from other autoimmune diseases in which research is decades ahead. For example, there is another pathomechanistically related autoimmune disease called Pemphigus, which affects the skin. Similar efforts towards using targeted therapies are going on there. I think in a few years from now, we may be able to treat patients with anti-nephrin antibodies very specifically and individually tailor therapies.
What’s next for you?
We plan to establish the anti-nephrin mouse model in my lab to figure out the exact disease mechanism and pursue the discovery of improved treatments, including molecules that might act as corticosteroid alternatives, or molecules that might interfere with the binding of the antibody to the podocyte so that the disease is cured mechanistically. We will also pursue studies on understanding the composition of specific anti-nephrin autoreactive B cells which can lead to specific treatments targeting the source without affecting other important B cell functions.
Paying attention to details led to a groundbreaking discovery that inspired others to continue researching in this area. Working on something that is immediately applicable to patients is very invigorating.
