NephCure Supported Research: The Nephrotic Syndrome Research Network April 2, 2018 by Lauren Eva The Nephrotic Syndrome Research Network is revolutionizing the field of glomerular kidney disease research. Now in its ninth year, the benefits of laying the groundwork for the Nephrotic Syndrome Research Network (NEPTUNE) are beginning to come into fruition. As NephCure CEO Josh Tarnoff notes, “It’s hard to overstate NEPTUNE’s impact on our understanding of FSGS and related syndromes. For example, one of the data sets presented by NEPTUNE at ASN Kidney Week 2016 provided the much-needed evidence correlating proteinuria levels to survival. This no doubt assisted the FDA to evolve their guidelines to accept proteinuria as a new surrogate endpoint for certain new drug approvals. This opened up the field for many new pharmaceutical companies to invest in drugs to treat FSGS and other causes of Nephrotic Syndrome. “Today, there are over 10 companies actively pursuing treatments for Nephrotic Syndrome diseases. NephCure is proud to support and partner with NEPTUNE and we’re grateful for how drastically NEPTUNE is changing the landscape for glomerular kidney disease.” To learn more about the current goals of NEPTUNE and how the study has evolved over the years, we recently sat down with Matthias Kretzler, MD and Professor of Internal Medicine/Nephrology and Computational Medicine and Bioinformatics at the University of Michigan, who has been leading NEPTUNE since its inception. Dr. Matthias Kretzler NephCure: Since 2009, you have led the Nephrotic Syndrome Research Network (NEPTUNE). What is the purpose of NEPTUNE? Dr. Kretzler: NEPTUNE set out to define what Nephrotic Syndrome diseases do to our patients in as a comprehensive of a way as possible. In a detailed interview, patients answer questions about how their disease manifested and how it has affected them. In addition, we capture blood, urine, and most importantly, kidney biopsy tissue samples in a way that allows us to very deeply analyze them to understand how the kidneys are damaged. We are very grateful for our patients who donate all this time to the study. NephCure: What insights has NEPTUNE data uncovered? Dr. Kretzler: We are now starting to understand what specific disease mechanisms we are seeing in Nephrotic Syndrome. We can see that many of the mechanisms are shared, not only within Nephrotic Syndrome, but with other glomerular diseases as well. On the other hand, even inside the conventional disease groups like FSGS, Membranous Nephropathy, etc., the NEPTUNE data sets are able to see distinct subgroups of patients who share a specific mechanism. We’ve accumulated follow-up data from more than 600 patients, so we now know how these various diseases change over time. The NEPTUNE research community is just starting to use advanced computational tools and machine learning approaches to define what the key trigger points are for disease initiation and progression. The exciting part is that in many instances, these pathways and trigger points are molecules which have already been successfully targeted by pharmaceutical companies. Most of the time, these drugs have been developed for another disease, like rheumatoid arthritis or diabetes. The NEPTUNE profiling allows us to identify these drugs and reach out to the companies to alert them, “Are you aware that your drug for rheumatoid arthritis might also help patients with Nephrotic Syndrome?” We can then start to work with them to develop pilot studies to test if these drugs might be successful for our patients. NephCure: I did not realize that NEPTUNE had identified actual molecular targets for potential treatments that already exist. That’s incredibly exciting! Dr. Kretzler: Yes. NEPTUNE data sets are starting to allow for the molecular definition of diseases . There has been a lot of infrastructure that needed to be established to do this type of molecular analysis, but the tools developed by the network now have a strong track record to robustly deliver tissue-based molecular information. This is very exciting. From a personal perspective, when I started my research in Dr. Wilhelm Kriz’s lab at the University of Heidelberg in 1987, I understood the scientific process as such: that we all contribute small steps to the scientific process, and what we do as scientists has an impact 5, 10, 20 years down the road towards developing treatments. This is now very different: If we get the right people together to align their forces behind a new treatment opportunity, we can now begin to move these things forward so quickly nowadays. It is stunning. As always with scientific progress, it is also a high-risk activity. But the alternative—to just watch the kidneys fail and to watch our patients go towards dialysis and renal transplantation—is not acceptable. We are committing everything we have to try to develop this knowledge so that we can test these innovative treatment strategies and see which of them will work. This is very new for our field. In oncology and rheumatology, this strategy towards drug development is already happening very successfully. We feel very strongly that for kidney disease, the time is now to test this approach. NephCure: Before NEPTUNE was created, had something like this existed for kidney disease? Dr. Kretzler: What’s different about NEPTUNE is that we can identify patients who have a specific disease-related molecule active at a given time inside their kidney. Using this patient data, we can hopefully fulfill the precision-medicine promise, at least to some extent: to provide the right drug, for the right patient, at the right time. The next round of NEPTUNE will transition from studying the disease as it progresses to testing different drugs in patients with a better understanding of the molecular mechanisms. In support of this strategy, several pilot projects have already been initiated with funding from NephCure. NephCure: Is NEPTUNE still actively recruiting? Dr. Kretzler: NEPTUNE is still very actively recruiting. We currently have 625 patients enrolled, and we need 15 more to reach our second funding-cycle goal. We envision that in the next funding cycle, we will recruit patients under treatment to learn what different drugs do to the kidney in molecular terms. NephCure: How many ancillary studies in total have used NEPTUNE resources? Dr. Kretzler: So far, more than 90 studies have used NEPTUNE data and bio-samples to do their research around the world. Many of those ancillary studies have been funded by NephCure. The NephCure-funded studies have been instrumental in energizing the scientific community. Through these studies, we have been able to attract many scientists who may not have otherwise studied glomerular diseases to this field. From the beginning, the idea was to align very tightly with NephCure. NephCure has always been a key player and partner in developing NEPTUNE. NephCure: It’s amazing when you consider how far NEPTUNE has pushed the field and the effort it must have taken, among so many different players, to bring it to fruition. Dr. Kretzler: The philosophy is that NEPTUNE is an instrument to empower cutting-edge research for the entire community. To build this kind of research infrastructure, not a single scientist has the time, energy or resources to do it. It requires a community effort. That is what has been so remarkable with NEPTUNE: that among many different people with very diverse backgrounds in science, the community has pulled together and has committed, for 9 years now, to join efforts. Every one of us had to invest in building this network for the future, and it’s very exciting that we feel that that investment is starting to deliver: that we have an opportunity to bring novel ideas and therapeutic concepts to our patients. Matthias Kretzler, MD, is the Warner-Lambert/Parke-Davis Professor of Internal Medicine/Nephrology and Computational Medicine and Bioinformatics at the University of Michigan. He received his medical training at the University of Heidelberg, Germany; Newcastle upon the Tyne in the UK; and at the University of Michigan. We are honored to have Dr. Kretzler as a member of the NephCure Scientific Advisory Board. To learn more about NEPTUNE or how you can get involved, please visit the NEPTUNE website.