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Gabriel Miguel Cara Fuentes @carafuentes_g – @carafuentes-neph.bsky.social

Dr. Cara Fuentes is an Assistant Professor of Pediatrics at The Ohio State University and a pediatric nephrologist and Director of the Glomerular Disease Clinic at Nationwide Children’s Hospital. He is a NIH-funded physician-scientist focused on finding novel targeted therapies and biomarkers to individualize care of children with nephrotic syndrome.

Competitors for the Minimal Change Disease Region

Team 1: Minimal Change Disease Diagnosis and Pathogenesis

vs

Team 2: Minimal Change Disease Relapse

Image generated by Evan Zeitler using DALLE-E 3, accessed via ChatGPT at http://chat.openai.com, February 2025. After using the tool to generate the image, Zeitler and the NephMadness Executive Team reviewed and take full responsibility for the final graphic image.

Idiopathic Nephrotic Syndrome (INS) is a rare, relapsing and debilitating disease with no cure or targeted therapies. In children, INS is the most common type of nephrotic syndrome and contrary to some beliefs, it is not an innocent disease. Patients with INS have an increased risk of infections, clots, acute kidney injury and chronic kidney disease. The clinical heterogeneity and biological complexity of the disease has hindered transformational discoveries for decades, and consequently, we struggle to find meaningful biomarkers and novel therapies to improve patient care.

Lessons From the Past

A hypothesis on the cause of INS was proposed in 1974 by Shalhoub, in which he suggested INS was a T-cell disorder based on the absence of immune deposits, the response to steroids that are known to modulate T cell-related disease, and the association with Hodgkin‘s disease. Shalhoub suggested that circulating factors released in response to T-cell activation increased the permeability of the glomerular basement membrane to plasma proteins.

In 1998, the sequencing of nephrin shifted the focus to the podocyte as the cellular target of T-cell-derived factors. While various factors were proposed, no convincing cause was identified despite research efforts, and the etiology of INS has remained a mystery. What have been the challenges? The human disease is rare and heterogenous, and experimental models are flawed. Thus, studies have been traditionally small, not reproducible and lacked translational methodology.

Without a deep understating of the disease pathobiology, we rely on clinical descriptors such as response to steroids and absence or presence of glomerulosclerosis (minimal change disease -MCD- vs focal segmental glomerulosclerosis -FSGS-, respectively) to guide clinical decisions and predict outcomes. While helpful, neither of these descriptors are definitive nor provide biological insights, making this terminology seem obsolete for the 21^st century. Likewise, our therapeutic approach has not changed significantly over time, except for the serendipitous observation that B-cell depleting drugs can be helpful. Still, corticosteroids remain as the gold standard therapy but, similar to other immunosuppressant drugs, are still used arbitrarily and associated with considerable side effects.

What can we learn from the past? To tackle INS, we need to work collaboratively, including large population studies and diverse scientific teams with expertise integrating clinical, translational and basic sciences. This approach will increase scientific rigor and reproducibility, ultimately leading to better patient care.

Lessons From the Present

In 2022, Weins et al identified circulating anti-nephrin antibodies and proposed these as candidate pathogenic factors in INS/MCD. This challenged the currently accepted paradigms for the last decades and opened a whole new field of research. This scientific earthquake was followed by reports from many other authors who identified additional  autoantibodies and provided experimental evidence of a causal role of anti-nephrin in INS/MCD. Is the role of B-cells a surprise? Yes and no. The lack of immune deposits have been always a strong argument against the role of B-cells, but more recently, the efficacy of B-cell depleting drugs and the B-cell phenotyping in INS patients has suggested otherwise. It is noteworthy that the observation of antibodies targeting nephrin and causing proteinuria and MCD-like lesions dates back to the late 1980’s and was followed by several publications suggesting a role of autoantibodies against podocytes. Who said paradigm shifting is easy? Bravo for Weins who persevered and “dusted” forgotten observations in INS.

As our understanding of disease is reshaped, changes in clinical practice will follow. Already, we are witnessing a transition from traditional trials comparing arbitrary steroid regimens to different B cell depleting drugs and novel targeted therapies. Results from ongoing trials will soon re-define how we treat patients. So, “old”, “small” and “personal” observations can still have the potential to be transformational if addressed rigorously and with perseverance.

Lessons For the Future

Most patients with INS have autoantibodies against podocytes, so is this puzzle resolved? We are far from that, I think. As a pediatric nephrologist, I am still trying to understand how auto-antibodies will change my practice. Will I be able to predict relapses or disease progression? Will B cell depleting agents replace calcineurin inhibitors and anti-metabolites?  Will following autoantibody titers help me  tapering therapies? While scientists across the world address these important questions, we should remain cautious. INS is a heterogeneous and biologically complex disease. Nobody can argue that B-cells and podocytes are key in the disease pathogenesis; however, is that all? I predict that other cell types and factors are yet to be discovered. For instance, what about pulmonary surfactants? In young children, most relapses are triggered by respiratory infections. Our group showed a causal link between circulating surfactants, nephrin phosphorylation and podocyte injury thereby providing a plausible explanation for such clinical association. What about the endothelium? Endothelial injury is linked to proteinuria in some kidney diseases. Could this be important for INS? Well, Ig M and some autoantibodies are already identified as circulating factors targeting the endothelium. Additionally, we and others showed that endothelial injury is underappreciated in INS, and that this is not simply a paraphenomenon. Also, is there a role for the complement cascade? Suddenly, we are realizing that the complement may be also involved in some patients.

As we dissect the molecular biology of INS, we are witnessing a rise in clinical trials aiming for diverse targets including immune cells, inflammation, and the complement. So, it is a fantastic time to be a (pediatric) nephrologist. Let’s embrace the moment but remaining focused on rigorous and collaborative research. If history taught us something about INS, it is to remain cautious and open-minded, because we never know when the next breakthrough is coming. My guess is that it won’t take another 24 years.

– Guest Post written by Gabriel Miguel Cara Fuentes

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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