Broad and Important Implications of a Rare Kidney Disease
By Erika Opingari
With a growing list of diseases and conditions ailing humankind today, it is understandable that the most prevalent ones take precedence in our minds and in our healthcare systems. While rare diseases, also known as orphan diseases, have much lower incidence rates, they may also have a lower standard of medical care supporting patients and families afflicted by them. When it comes to research, rare diseases are untapped ground, presenting a rewarding opportunity for scientists and clinicians to make discoveries that have a profound impact on patient outcomes.
Trained in Germany, Dr. Christoph Licht is an expert nephrologist appointed at The Hospital for Sick Children and Toronto General Hospital, and full professor of paediatrics at the University of Toronto. Actively involved in clinical and basic science research, Dr. Licht focuses his expertise and efforts on rare complement-mediated kidney diseases, namely atypical hemolytic-uremic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN, or today: C3 glomerulopathy, C3G). Most often caused by a genetic mutation or autoantibodies, aHUS can manifest anytime from childhood to senior life, with an annual incidence estimated to be about two cases per 1,000,000 people.1 The first report of a genetic defect in the complement system was published in 1998, a milestone which opened the doors for patient screening and gathering more data.2 Today, half a dozen mutations and anti-complement factor H (FH) autoantibodies have been identified that result in dysregulation, and more specifically, upregulation of the complement system.
The complement system is a principle contributor to our innate immunity, which is constantly present and ubiquitously active. All tissues are covered with low-grade active complement proteins that serve to identify and distinguish self from non-self-tissue. As Dr. Licht passionately describes, “It’s great biology, it’s ancient biology, which means it’s powerful biology.” The microvasculature of the kidneys is particularly susceptible to complement-mediated thrombotic microangiopathy. Essentially, overactivation of the complement system causes endothelial damage and clot formation, leading to kidney failure and—in extreme cases—even death.
By manipulating endothelial cells to mimic the inside of a blood vessel, Dr. Licht’s lab aims to identify what occurs to tissues attacked by the complement system, with a recent focus on changes in energy consumption and mitochondrial function. Historically, the teaching has been that once the complement system is activated, cells die, and the dead cell surface is the starting point for inflammation and coagulation. The truth however is likely more complex. Once activated on the cell surface, complement proteins form membrane attack complexes which create pores in the cell’s membrane. Dr. Licht’s lab has demonstrated that these pores result in a rapid and massive influx of calcium into the cells, which consequently impairs mitochondrial function and reduces adenosine triphosphate (ATP) reservoirs (the main energy currency of cells). In response, cells go into a state of hibernation, during which they use minimal energy and activate replacement mechanisms like autophagy (cellular degradation) and mitophagy (mitochondrial degradation), as has been demonstrated by Dr. Licht’s lab.
Dr. Licht’s research indicates that while these cells are severely impacted by the complement attack, they also initiate survival mechanisms such as suspending certain functions like motility in attempts to conserve energy and survive. While being motile allows viable endothelial cells to minimize lesions in the monolayer, it is an energy-demanding process that the cells can no longer afford. Therefore, rather than a dichotomous outcome of life or death, endothelial cells have evasion strategies that allow them to survive a complement attack and avoid apoptosis. What remains unexplored is the extent to which these cells can survive under complement stress. Dr. Licht aims to answer this question, with projects currently underway.
As a ubiquitous modulating system, the complement system likely has implications in many more contexts than we appreciate today. Looking outside the kidneys, Dr. Licht hypothesizes that complement-mediated mitochondrial dysfunction is likely a common mechanism across various tissues, particularly impacting high turnover and energy sensitive tissues such as neuronal, retinal and muscle tissue. Accordingly, Dr. Licht explains that the field is “in a period of transition from a very finite and limited number of well-defined complement-mediated diseases, to an increasing list of conditions in which the complement system plays a role.”
With a growing spectrum of conditions and broader applicability comes an opportunity for greater impact. Furthermore, as the understanding of these diseases grows, there is a conceptual transition in how to manipulate and treat complement dysregulation. As Dr. Licht explains: “Smart treatment in the future will include tools to identify where [the complement] plays a role, assess its function and dysfunction, and then define the windows of opportunity for complement-modulating treatment. Rather than shutting down the entire system, the way forward may be modulating one effector arm or a few factors that are key players in some conditions, leaving the rest of the cascade alone.” The significance of this research is not only knowledge development, but it’s also translatability into improved patient outcomes.
The only treatment currently available for aHUS is the monoclonal anti-C5 antibody, eculizumab, a first-in-class drug that inhibits complement activation, thus effectively and safely treating aHUS.3,4 Since its approval in 2011 by the Food and Drug Administration and the European Medical Association, followed in 2013 by Health Canada, eculizumab has single-handedly transformed the outcomes of patients and the epidemiology of the disease.3 Just a few doses of eculizumab can drastically change the health status of patients, allowing them to lead a normal life with regular treatment and monitoring. However, this treatment comes at a staggering cost of $500,000 to $700,000 per patient per year, making it one of the most expensive drugs on the market.5-7 Thirteen years later, the sole company manufacturing this drug, Alexion, continues to hold a monopoly over the market. With their patent protection coming to an end soon, several new companies are emerging with similar drugs, hopefully improving accessibility for patients in the future.
“There’s a major international sense of dissatisfaction, since entire countries are cut off access to this drug—China, India, most of Russia, and Africa. This is a treatment that’s currently available and accessible to First World countries only. And that is just not acceptable” says Dr. Licht.
The cost of treatment is understandably a major challenge in patient management. The first time Dr. Licht applied for hospital coverage of treatment for a young patient with aHUS, he was turned down— “the cost of treatment for one patient would be the equivalent of keeping an obesity clinic open. Now we treat one patient and let down many more on the other side.” This exemplifies the problem experienced by health care systems around the world—with limited resources, what is the most ethical and sound choice?
“It also raises a point that there is a general problem regarding orphan diseases and related treatments.” Dr. Licht emphasizes that we must engage in more public conversations and change the concept around orphan diseases and drug development. “The current system is unsustainable, unaffordable and exclusive to certain groups. There is a big problem of lack of justice,” says Dr. Licht. He highlights that although drug development is costly, we need to find a way to improve accessibility for patients.
“Overpriced drugs are prohibitive in terms of what physicians would naturally be doing and creates challenges for the field moving forward” Dr. Licht stated. With limited access to eculizumab, physicians cannot use it in conditions that would likely be responsive, thereby limiting the benefit of treatment and opportunities for learning and discovery. The financial barrier not only affects patients and their families, but the medical decisions of the physicians involved in their care.
Research and development in complement-mediated diseases clearly has a long way to go. By better understanding the mechanism of disease, we can develop better criteria and tools for detection, monitoring, and treatment of complement-mediated diseases. Although colloquially referred to as orphan diseases, patients and their families are not alone in their medical journey, thanks to the dedication and advocacy of clinicians and scientists, like Dr. Licht, around the world.
- Constantinescu AR, Bitzan M, Weiss LS, Christen E, Kaplan BS, Cnaan A, et al. Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis. 2004 Jun;43(6):976–82.
- Warwicker P, Goodship TH, Donne RL, Pirson Y, Nicholls A, Ward RM, et al. Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int. 1998 Apr;53(4):836–44.
- FDA Approves Conversion of Soliris® (eculizumab) Accelerated Approval in aHUS to Regular Approval for the Treatment of Patients with aHUS | Alexion Pharmaceuticals, Inc [Internet]. [cited 2019 Dec 6]. Available from: https://news.alexion.com/press-release/product-news/fda-approves-conversion-soliris%C2%A0eculizumab-accelerated-approval-ahus-regu
- Licht C, Greenbaum LA, Muus P, Babu S, Bedrosian CL, Cohen DJ, et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int. 2015 May;87(5):1061–73.
- The Lancet Haematology. The rising cost of orphan drugs. The Lancet Haematology. 2015 Nov 1;2(11):e456.
- Crowe K. How a pharmaceutical firm priced its life-saving drug at $500K a year | CBC News [Internet]. CBC. 2015. Available from: https://www.cbc.ca/news/health/how-pharmaceutical-company-alexion-set-the-price-of-the-world-s-most-expensive-drug-1.3125251
- World’s most expensive drug — which costs up to $700,000 per year — too expensive, Canada says | National Post [Internet]. Available from: https://nationalpost.com/health/worlds-most-expensive-drug-prescription-that-costs-up-to-700000-per-year-too-expensive-canada-says