Tackling Inflammation and Equity

Tackling Inflammation and Equity

By Diana Hamdan

Did 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 ischemia-reperfusion 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.

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

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 Slit2, 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, 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 anti-inflammatory functions.

Photo by Avideh Gharehgazlou

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 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.”

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IMS writer Diana Hamdan is a recent MSc graduate continuing her work on molecular mechanisms of immune cell trafficking in vascular inflammation with Dr. Lisa Robinson at the Hospital for Sick Children. Outside the lab, Diana is involved in initiatives that promote sustainable practices in urban environments.

 

 

 

References

1. Manns B, McKenzie SQ, Au F, Gignac PM, Geller LI, Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD) Network. The financial impact of advanced kidney disease on Canada Pension Plan and private disability insurance costs. Canadian journal of kidney health and disease. 2017 Apr 13;4:2054358117703986.
2. Organ replacement in Canada: CORR annual statistics, 2018, https://www.cihi.ca/en/organ-replacement-in-canada-corr-annual-statistics-2018, supplemented with data collected by the Quebec Branch of The Kidney Foundation of Canada as provided by renal units. *Excludes Québec.
3. Robinson LA, Nataraj C, Thomas DW, Howell DN, Griffiths R, Bautch V, Patel DD, Feng L, Coffman TM. A role for fractalkine and its receptor (CX3CR1) in cardiac allograft rejection. The Journal of Immunology. 2000 Dec 1;165(11):6067-72.
4. Fong AM, Robinson LA, Steeber DA, Tedder TF, Yoshie O, Imai T, Patel DD. Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow. Journal of Experimental Medicine. 1998 Oct 19;188(8):1413-9.
5. Tole S, Mukovozov IM, Huang YW, Magalhaes MA, Yan M, Crow MR, Liu GY, Sun CX, Durocher Y, Glogauer M, Robinson LA. The axonal repellent, Slit2, inhibits directional migration of circulating neutrophils. Journal of leukocyte biology. 2009 Dec;86(6):1403-15.
6. Mukovozov I, Huang YW, Zhang Q, Liu GY, Siu A, Sokolskyy Y, Patel S, Hyduk SJ, Kutryk MJ, Cybulsky MI, Robinson LA. The neurorepellent slit2 inhibits postadhesion stabilization of monocytes tethered to vascular endothelial cells. The Journal of Immunology. 2015 Oct 1;195(7):3334-44.
7. Chaturvedi S, Yuen DA, Bajwa A, Huang YW, Sokollik C, Huang L, Lam GY, Tole S, Liu GY, Pan J, Chan L. Slit2 prevents neutrophil recruitment and renal ischemia-reperfusion injury. Journal of the American Society of Nephrology. 2013 Aug 1;24(8):1274-87.
8. Patel S, Huang YW, Reheman A, Pluthero FG, Chaturvedi S, Mukovozov IM, Tole S, Liu GY, Li L, Durocher Y, Ni H. The cell motility modulator Slit2 is a potent inhibitor of platelet function. Circulation. 2012 Sep 11;126(11):1385-95.
9. Kaths JM, Echeverri J, Goldaracena N, Louis KS, Chun YM, Linares I, Wiebe A, Foltys DB, Yip PM, John R, Mucsi I. Eight-hour continuous normothermic ex vivo kidney perfusion is a safe preservation technique for kidney transplantation: a new opportunity for the storage, assessment, and repair of kidney grafts. Transplantation. 2016 Sep 1;100(9):1862-70.
10. Kaths JM, Hamar M, Echeverri J, Linares I, Urbanellis P, Cen JY, Ganesh S, Dingwell LS, Yip P, John R, Bagli D. Normothermic ex vivo kidney perfusion for graft quality assessment prior to transplantation. American Journal of Transplantation. 2018 Mar;18(3):580-9.
11. Alexander C, Bendiner J. Canada’s Literacy and Numeracy Challenge Worsens. TD Economics; 2013.