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Accelerating the Discovery of Anti-Fibrotic Therapies for Chronic Kidney Disease

By Alexa Desimone

Fibrotic disorders are becoming increasingly prevalent; they take many forms and are often life threatening. It is estimated that fibrosis accounts for almost half the chronic diseases afflicting industrialised countries.1 Chronic kidney disease (CKD) is one of the most devastating and common examples of fibrotic disease.2,3 In the kidney, fibrosis is characterized by the accumulation of extracellular matrix proteins, typically in the glomerulus and tubulointerstitium, which inevitably infringes on nearby structures, resulting in hypoxia, tubular atrophy, and inflammatory cell infiltration.4 With time, the formation of fibrotic lesions leads to irreversible end-stage kidney failure. Unfortunately, four million Canadians are currently living with CKD, with the majority requiring dialysis or kidney transplantation.5 Despite its prevalence, therapeutic strategies targeting profibrotic mechanisms in CKD are lacking.

Dr. Richard E. Gilbert, an endocrinologist at St. Michael’s Hospital in Toronto, has dedicated his professional career to identifying therapeutic strategies for the prevention and treatment of chronic fibrotic disorders, focussing predominantly on CKD and heart failure. He is particularly interested in these disorders in the diabetic setting given that diabetes is present in approximately 30-50% of all patients with either heart failure or CKD. Dr. Gilbert is a Tier 1 Canada Research Chair in Diabetes Complications, Professor of Medicine at the University of Toronto, and Head of the Division of Endocrinology at St. Michael’s Hospital/Unity Health Toronto.

Growing up in Adelaide, a small city in South Australia, Dr. Gilbert completed his medical training at Flinders University. Excited by the prospect of continuing in clinical medicine while also pursuing his research interests, he accepted an offer as a one-year lecturer at London University in London, England. As Dr. Gilbert described, “The salary was barely enough to live on but the opportunity it afforded me in the academic, social and societal spheres was immeasurable”. This was a pivotal moment in Dr. Gilbert’s career. Rather than staying on a predictable and linear path, he made a bold choice that would enrich his academic and life experiences.

Returning to Australia, he completed his medical fellowship and doctoral studies in the clinical and molecular aspects of diabetic kidney disease and established a highly productive research laboratory at St. Vincent’s Hospital in Melbourne, Australia. But it was time for Dr. Gilbert to broaden his horizons once again by seeking to do a sabbatical in Toronto where his wife, Susan, was from. Rather than offers for his intended sabbatical, Dr. Gilbert was invited to apply for newly available clinician-scientist positions at two University of Toronto institutions. “Coming to a city with such great research, collegiality, and collaboration made the decision easy” said Dr. Gilbert. So, in 2006 he set up his laboratory and took up his post at St. Michael’s Hospital as a clinician-scientist.

The pathogenesis of diabetic kidney and heart disease, encompassing both glucose-dependent and glucoseindependent pathways, requires a multifaceted approach to establish therapeutic strategies.⁶ In the kidney, fibrosis impairs filtration and tubular cell function, whereas in the heart, it impairs both systolic and diastolic function with stiffening and impaired contractility of

DR. RICHARD E. GILBERT MD, FRCPC, FRACP, FACP, FASN, PhD

Professor of Medicine, University of Toronto Head of the Division of Endocrinology, St. Michael’s Hospital Canadian Research Chair in Diabetes Complications

It’s possible to be a dedicated academic and devoted clinician, but to also be cognisant of the need to engage with industry and the business community in order to progress your ideas towards the clinic.

the left ventricle.⁷ While investigating the pathogenesis of fibrosis is of great interest to Dr. Gilbert, his real desire was to develop new therapies that could be used to treat patients. With this in mind, he co-founded a biotechnology company called Fibrotech Therapeutics which attracted NIH funding to progress its lead compound, FT011, into early human studies. In pre-clinical studies, FT011 has demonstrated anti-fibrotic and antiinflammatory properties that have shown to be useful in treating chronic heart failure associated with diabetic kidney disease.⁸ After Fibrotech was sold to Shire, a large, multi-national pharmaceutical company, Dr. Gilbert, believing that a single drug was unlikely to cure a complex disease process such as fibrosis, continued to investigate novel approaches to combat fibrotic disease.

In 2016, Dr. Gilbert along with three other co-principal investigators were awarded a $1-million Transformational

Diabetes Team Research Grant from the University of Toronto’s Banting and Best Diabetes Centre. This funding was used as the foundation for another endeavor to develop new anti-fibrotic therapies. Along with funding from MaRS Innovation and an investment from another biotechnology company, Evotech, Fibrocor Therapeutics began utilizing archival kidney biopsy tissue to uncover transcriptomic changes that are linked to fibrosis. One of the very first analyses of the data uncovered the discoidin domain receptors (DDRs), unique tyrosine kinase receptors that signal in response to nondiffusible collagens and have been shown to be upregulated in fibrotic diseases.⁹ Their team identified DDRs as a close correlate of declining kidney function and the extent of fibrosis. With the help of Evotech, Fibrocor’s drug development partner, they hope to develop inhibitors of DDR to treat, prevent, and possibly reverse fibrotic disease.

Images provided by Dr. Gilbert

Dr. Gilbert embodies the concept of bench-to-bedside medicine in its truest sense. With a strong background in basic research, he knew that his findings could benefit innumerable patients with CKD. He took it upon himself to try and turn his discoveries into therapeutic agents that help patients. “It’s possible to be a dedicated academic and devoted clinician, but to also be cognisant of the need to engage with industry and the business community in order to progress your ideas towards the clinic”, says Dr. Gilbert. He hopes to inspire young clinician-scientists to always look for opportunities that enrich your life experience as well as your professional life.

References

1. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117(3):524-529. 2. Hewitson TD. Fibrosis in the kidney: is a problem shared a problem halved? Fibrogenesis Tissue Repair, 2012;5, S1:S14. 3. Canadian Institute for Health Research. Annual Statistics on Organ

Replacement in Canada Dialysis, Transplantation and Donation, 2008 to 2017. CIHI Snapshot, December 2018. Available from:https:// secure.cihi.ca/free_products/snapshot-corr-2018-en.pdf. 4. Gilbert RE, Zhang Y, Williams SJ, et al. A purpose-synthesised anti-fibrotic agent attenuates experimental kidney disease in the rat.

PLoS One, 2012:7(10), e47160. 5. Manns, B., McKenzie, S.Q., Au, F., et al. The financial impact of advanced kidnet disease on Canada pension plan and private disability insurance costs. Can J Kidney Health Dis, 2017:4, 1-11. 6. Kelly DJ, Zhang Y, Hepper C, et al. Protein kinase C beta inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continues hypertension. Diabetes, 2003:52, 512-518. 7. Yuen DA, Connelly KA, Zhang Y, et al. Early outgrowth cells release soluble endocrine antifibrotic factors that reduce progressive organ fibrosis. Stem Cells, 2013:31(11), 2408-2419. 8. Zhang Y, Edgley AJ, Cox AJ, et al. FT011, a new anti-fibrotic drug, attenuates fibrosis and chronic heart failure in experimental diabetic cardiomyopathy. E J Heart Fail, 2012:14, 549-562. 9. Borza CM, Pozzi A. Discoidin domain receptors in disease. Matrix

Biol, 2014:34, 185-192. 10. Zhang Y, Connelly KA, Thai K, Wu X, Kapus A, Kepecs D, Gilbert

RE. Sirtuin 1 Activation Reduces Transforming Growth Factor-β1–Induced Fibrogenesis and Affords Organ Protection in a Model of Progressive, Experimental Kidney and Associated Cardiac Disease. The American journal of pathology. 2017 Jan 1;187(1):80-90.

From infancy to adulthood: A molecular look at kidney malformations

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common form of malformation at birth, identified in over 1% of overall live births and accounting for up to 23% of overall birth defects. CAKUT represent the cause of 40-50% of pediatric end-stage renal disease worldwide.1 While some CAKUT are treatable-albeit with long term health consequences-others are extremely life threatening.2 UofT researchers are using genetically modified mice and human kidney organoids grown from patients’ urine samples to understand the molecular mechanisms underlying kidney disease. Their goal is to one day develop individualized treatments that target these molecular pathways in pediatric patients. By Nadia Boachie

The causes of kidney failure vary from infancy to adulthood. Before age five, congenital malformations of the kidney and urinary tract are the leading causes. From ages five to 14, it is most commonly caused by nephrotic syndrome, systemic diseases, and hereditary diseases such as autosomal dominant polycystic kidney disease. At around 15 years to early adulthood, diseases that affect the glomeruli—tiny ball-shaped structures in the kidney composed of capillary blood vessels that are involved in the filtration of the blood to form urine— become the leading cause of kidney failure.3

With so many different contributors and causes of kidney failure in the pediatric population, researchers are trying to better understand the molecular mechanisms of kidney development that occur prenatally and postnatally, with a goal to treat patients. The IMS Magazine had the pleasure of sitting down with Pediatric Nephrologist and Senior Scientist at The Hospital for Sick Children, Dr. Norman Rosenblum. He completed his MD at Dalhousie University and postgraduate clinical and research training at Children’s Hospital and Harvard Medical School, and has been conducting research in nephrology for his entire career as a clinician-scientist. Dr. Rosenblum set up his lab in 1993 and his first graduate unit appointment in 1995 was with The Institute of Medical Sciences (IMS).

Dr. Rosenblum began using mouse models as well as other experimental methods to ask three important questions; ‘How is formation of the kidney accomplished?’, ‘What are the cellular and molecular mechanisms underlying kidney malformation?’, and ‘How can we use human genetics and experimental nephrology to inform our understanding of kidney development and human disease?’

To address these questions, Dr. Rosenblum’s lab “focuses on different signalling pathways, both alone and together during the development of the kidney in the mouse” he explained. Specifically, the lab looks at pathways controlled by Bone Morphogenetic Proteins (BMPs), Hedgehogs (Hh), and Wnt proteins during normal kidney formation and renal malformation.4 Hedgehog signaling has been of particular interest, as hedgehog proteins are important for tissue patterning and cell differentiation. They also transduce cellular signals via the GLI protein family of transcription factors. “Everything we seem to touch, from how progenitor cells are differentiated to specific kidney elements, variation in nephron number, or interactions between different tissue elements - in whatever we inquire about, there seems to be a story about how hedgehog signaling is involved” says Dr. Rosenblum.

Photo by Nadia Boachie

DR. NORMAN ROSENBLUM, MD

Pediatric Nephrologist at The Hospital for Sick Children Senior Scientist at The Hospital for Sick Children Professor of Pediatrics, Physiology, and Laboratory Medicine and Pathobiology at the University of Toronto

In a 2018 paper published in Journal of American Society for Nephrology, Dr. Rosenblum and his collaborators used patients’ specimens and mouse models to better understand the pathogenesis of ureteropelvic junction obstruction, the most common form of congenital urinary tract obstruction. The mice in this study were genetically modified to be deficient for the Hedgehog target, Ptch1. Rosenblum and collaborators analyzed obstructive ureteric tissue obtained from children with congenital intrinsic ureteropelvic junction obstruction and discovered that molecularly, these human samples were similar to what

This is an image captured and stained by members of Dr. Rosenblum’s lab. It is a stitched wholemount kidney organoid generated from blood-derived induced pluripotent stem cells. DAPI (blue) marks the nuclei of all cells, WT1 (red) marks renal podocytes, and ECAD (green) marks distal tubular epithelial cells.

was observed in Ptch1-deficient mice. Their results demonstrate a Hedgehogdependent mechanism underlying urinary tract blockage. In another recent 2018 publication in Development, they found a mechanism by which Hedgehog-GLI signaling in Foxd1-positive stromal cells, via TGFβ signaling, controls the number of nephrons formed in the kidney.5 “We keep working at [hedgehog] because the story continues to unfold, in a very interesting way” he explains.

Dr. Rosenblum clarifies that experiments in mice are vital but are not the entire picture. “There are important differences in what happens in mice and what happens in humans. Same gene, same mutation, doesn’t look the same in terms of what the phenotype is in humans versus mice” he explains, “We really wonder why that is. So, we are using human organoids as a way to model these things and inquire further into mechanisms of human disease” he adds.

Recently, the Rosenblum lab and collaborators were able to isolate human urine cells (UCs) from pediatric urine specimens. These urine samples were reprogrammed into urinary induced pluripotent stem cells from which human kidney organoids were generated.6 “When you take urine, even small amounts, and put it on a plate, epithelial cells grow. What you then can do is treat those cells with plasmids that contain four factors that were described in Nobel winning work7 to convert the cells from a differentiated cell to a pluripotent cell. Once you have that pluripotent cell, then you can direct that cell to differentiate in various ways using other factors” Dr. Rosenblum explained. He further elaborated that “even though [the organoid] is a very immature kidney tissue, it is human tissue, and [it is] from the very patients that we would be interested in.” This is a big step in the right direction for individualized kidney treatments.

There are still major challenges in this field of research. A healthy and functioning kidney requires formation of a critical number of nephrons; they are necessary to drain urinary filtrate into the ureter towards the bladder. A large body of epidemiological studies have shown that the number of nephrons that you are born with varies tremendously in the population.8 There may be as much as a six-fold difference between individuals. Some may be born with 200,000 nephron elements, and others with about 1.8 million. “Clinically, we don’t even have a method to measure the number of nephrons elements an individual is born with” explains Dr. Rosenblum. This poses an issue when trying to identify infants that may have potential issues with kidney development in the future. Dr. Rosenblum’s lab is trying to find non-invasive ways to determine nephron number. “We are aiming to determine biomarkers that tell us this information, for example, based on their number of nephrons we’ll be able to say ‘well this person may be at higher risk [for kidney disease/malfunction] so we should be aware of it,’” he explains.

Dr. Rosenblum’s impressive list of publications and his successful career as a clinician-scientist seems to be made possible because of his well-roundedness. Outside of the lab, Dr. Rosenblum is a seasoned cello player, an instrument he has played since the age of 14. His passion for classical music drives him to continue to practice and play with other musicians to this day. He wants students and young researchers to know that in their professional careers, they should go after what they are passionate about. He also advised that researchers “find other things to do which cater to other parts of you,” and to spend time on that too. Lastly, he added that “the management of time and energy is a big skill and maybe one of the most important skills that people have. Just because you work long doesn’t mean you work well.” These pieces of advice seem to be how Dr. Rosenblum continues to thrive in his scientific endeavours.

References

1. Sanna-Cherchi, Simone, Pietro Ravani, Valentina Corbani, Stefano Parodi, Riccardo Haupt, Giorgio Piaggio, Maria L. Degli Innocenti et al. “Renal outcome in patients with congenital anomalies of the kidney and urinary tract.” Kidney international 76, no. 5 (2009): 528-533. 2. Kidney Disease in Children [homepage on the internet] National

Institute of Diabetes and Digestive and Kidney Diseases, U.S. Department of Health and Human Services, 1 Mar. 2014, Available from: http//www.niddk.nih.gov/health-information/kidney-disease/ children. 3. National Institutes of Health. National Institute of Diabetes and

Digestive and Kidney Diseases. United States Renal Data System. 1993 Annual Data Report. 1993 Mar: 55-67. 4. Norman Rosenblum Lab [homepage on internet]” Rosenblum Lab,

Available from: http//lab.research.sickkids.ca/rosenblum/. 5. Rowan CJ, Li W, Martirosyan H, Erwood S, Hu D, Kim YK,

Sheybani-Deloui S, Mulder J, Blake J, Chen L, Rosenblum ND. Hedgehog-GLI signaling in Foxd1-positive stromal cells promotes murine nephrogenesis via TGFβ signaling. Development. 2018 Jul 1;145(13):dev159947. 6. Mulder J, Sharmin S, Chow T et al. Generation of infant-and pediatric-derived urinary induced pluripotent stem cells competent to form kidney organoids. Pediatric Research. 2019 Oct 19:1-0. 7. Takahashi K, Okita K, Nakagawa M, Yamanaka S. Induction of pluripotent stem cells from fibroblast cultures. Nature protocols. 2007

Dec;2(12):3081. 8. Wang X, Garrett MR. Nephron number, hypertension, and CKD: physiological and genetic insight from humans and animal models. Physiological genomics. 2017 Jan 27;49(3):180-92.

Dr. Rosenblum’s lab characterizes how healthy kidneys develop in order to understand what can go wrong in patients with congenital anomalies. This is an image showing a mouse embryonic kidney histological section stained for DAPI (blue) which marks the nuclei of all cells, PBX1 (pink) which marks stromal progenitor cells, SALL1 (green) which marks both stromal, and nephrogenic progenitor cell and the orange cells in the periphery are both Sall1+ and Pbx1+.

By Erika Opingari W ith 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 complementmediated 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.

Broad and Important Implications of a Rare Kidney Disease

The complement system is a principle contributor to our innate immunity, which is constantly present and ubiquitously active. All tissues are covered with lowgrade 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 complementmediated 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 complementmediated 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 welldefined 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 singlehandedly 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 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

Photo by Krystal Jacques

DR. CHRISTOPH LICHT MD, FRCP(C), FASN Staff Physician, Division of Nephrology, The Hospital for Sick Children and Division of Nephrology, Toronto General Hospital Director, Dialysis and Apheresis Program Senior Scientist, Cell Biology Program, Peter Gilgan Centre for Research and Learning Professor, Department of Paediatrics, University of Toronto

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 complementmediated 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.

References 1. 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. 2. 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. 3. 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-conversionsoliris%C2%A0eculizumab-accelerated-approval-ahus-regu 4. 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. 5. The Lancet Haematology. The rising cost of orphan drugs. The

Lancet Haematology. 2015 Nov 1;2(11):e456. 6. 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-pharmaceuticalcompany-alexion-set-the-price-of-the-world-s-most-expensivedrug-1.3125251 7. 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-expensivedrug-prescription-that-costs-up-to-700000-per-year-too-expensivecanada-says

Tackling Inflammation and Equity

By Diana Hamdan D id you know that a person with kidney disease can lose more than 50% of their kidney function before any symptoms appear? One in ten Canadians lives with kidney disease1, an almost 35% increase since 2008.2 Patients with end-stage kidney disease are either treated with dialysis, or if deemed eligible, receive a kidney transplant. Following an initial series of tests, individuals are placed on a waiting list and may wait several years before receiving a transplant, depending on the availability and compatibility of donor kidneys. Kidney transplantation is further complicated by ischemiareperfusion injury (IRI), an inevitable consequence of organ transplantation. IRI is characterized by restricted blood supply to the organ followed by the restoration of blood flow and re-oxygenation. Renal IRI can trigger inflammatory molecular cascades, which puts the recipient at risk of developing acute kidney injury (AKI), ultimately leading to kidney failure.

“Despite our knowledge of the detailed biology of kidney disease, we have limited tools that effectively inhibit the progression of kidney disease, and the treatments available are mainly supportive,” says Paediatric Nephrologist and Senior Scientist, Dr. Lisa Robinson. Clinical interventions that mitigate organ injury as well as signaling molecules involved in the migration of immune cells during inflammation have been the focus of her research over the last two decades.

Dr. Lisa Robinson is a University of Toronto Professor in the Department of Paediatrics, Head of the Division of Nephrology at the Hospital for Sick Children (SickKids), and a Senior Scientist in the Cell Biology program at the SickKids Research Institute. She received her undergraduate and medical degrees at the University of Toronto. She completed an internal medicine internship at the Toronto General Hospital (TGH) followed by a Paediatrics residency at the University of Western Ontario. Following her residency, she held a fellowship in paediatric nephrology at Duke University in North Carolina, where she completed her research training in the Departments of Immunology and Medicine, as a part of the Pediatric Scientist Development Program. In 1991, she held a junior faculty position at the Duke University Medical Center before returning to Toronto in 2002, joining SickKids as a Nephrologist and Scientist.

Dr. Robinson’s primary research interests lie in inflammation in the context of acute kidney injury, kidney fibrosis, and atherosclerosis. One specific area of her research is aimed at understanding mechanisms that regulate immune cell trafficking to inflamed tissue. Her work and others have shown that a blood vessel wall protein, known as fractalkine, is highly expressed in inflamed tissues and plays a key role in transplant rejection and atherogenesis. 3,4 Despite its wide involvement in inflammatory disease, little is known about the molecular mechanisms regulating the expression and activity of fractalkine. The Robinson Lab is actively studying molecular players and signaling pathways involved in the production of fractalkine.

Another aspect of Dr. Robinson’s research harnesses endogenous signaling cues that our bodies normally use to limit excessive inflammation as novel therapeutics for renal and vascular injury. The highly conserved, secreted Slit proteins and their Robo receptors were initially characterized as neuronal migration repellents in the developing nervous system of Drosophila melanogaster (fruit flies). Recent reports have pointed to the role of Slit and Robo outside of development, particularly in inflammation. Dr. Robinson’s team found that a specific isoform of the Slit protein group, known as Slit 2 , inhibits migration of multiple subsets of white blood cells towards inflammatory mediators by binding to cell surface receptor, Robo-1. 5-7 Using a mouse model of induced renal IRI, they also showed that exogenous administration of Slit2 markedly reduced acute kidney injury and curbed collagen deposition and fibrosis. 7 Additionally,

Photo by Avideh Gharehgazlou

Lisa Robinson, MD, FRCPC Professor, Department of Paediatrics, Faculty of Medicine Division Head of Nephrology, The Hospital for Sick Children (SickKids) Senior Scientist, SickKids Research Institute Associate Dean, Inclusion and Diversity, Faculty of Medicine

Slit2 has been shown to act as a potent anti-platelet agent in vivo and in vitro, an invention Dr. Robinson patented. 8 “This is super exciting because Slit2 is naturally produced in the human body, making it a promising therapeutic tool in the clinic.” Currently, Dr. Robinson and her team are working on determining the smallest portion of Slit2 required to exert its antiinflammatory functions.

As for her translational research, Dr. Robinson, in collaboration with Transplant Surgeon Scientist Dr. Markus Selzner at the University Health Network (UHN), has pioneered normothermic ex vivo kidney perfusion (NEVKP) as a novel approach for renal graft preservation. Normothermic perfusion is a method of maintaining organ viability at physiologic temperatures (35-38°C), as opposed to the cold temperatures traditionally used in hypothermic perfusion (0-8°C). In a pig transplantation model, NEVKP was shown to minimize renal IRI damage and improve graft functional recovery compared to cold storage. 9, 10 In late 2017, NEVKP was successfully used on a human kidney graft at TGH.

Beyond her research interests, Dr. Robinson is an advocate for diversity and equitable access to science. Children in low-income neighbourhoods of Ontario have consistently scored lower in the compulsory grade ten literacy test compared to their more affluent counterparts. This has been linked to elevated levels of high school incompletion, lower post-secondary

Photo by Avideh Gharehgazlou

matriculation, poorer health outcomes and a decreased level of wellbeing. 11 Given the gravity of the disparity that exists in Ontario, Dr. Robinson founded the Manulife Kids Science & Technology program at SickKids in 2006, which provides at-risk middle and high school students in disadvantaged neighbourhoods with an equitable access to interactive science opportunities. The program has reached over 20,000 students across Ontario by the spring of 2018. Additionally, Dr. Robinson also founded the Student Advancement Research (StAR) program at SickKids, which provides under-represented minority high school students with a six-week paid summer internship in research and clinical shadowing. Through these programs, Dr. Robinson hopes to broaden the youths’ perspective on Science, Technology, Engineering and Mathematics (STEM), and encourage them to attain higher education and employment in the STEM field.

In 2016, Dr. Robinson was appointed the Chief of Diversity Officer, the first position of its kind in a Canadian medical school. “There was a growing recognition of the disparities in diversity between the Faculty of Medicine’s demographic and that of our multicultural Toronto community”, she explains. She helped establish the Diversity Advisory Council, which involves members across the Faculty of Medicine as well as external partners, such as the Toronto Academic Health Sciences Network (TAHSN), who share strategies to identify and break down the barriers to inclusion and diversity. As a clinician scientist, Dr. Robinson believes in the importance of gathering data to drive our knowledge of the instances and patterns of discrimination, harassment and exclusion. By conducting surveys aimed at all members in the Faculty of Medicine, including medical students and residents, post-docs, graduate students, faculty and other staff members, the Office of Inclusion and Diversity is working on designing programs and policies that promote an inclusive learning and working environment. With her new title as Associate of Inclusion and Diversity, Dr. Robinson continues to promote equity, inclusion and diversity in admissions, education, and recruitment at the University of Toronto Faculty of Medicine. “If we truly strive for excellence in training our future care providers and scientists, we have to embrace inclusivity.”

References 1. Manns B, McKenzie SQ, Au F, Gignac PM, Geller LI, Canadians

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