Laura Whittall, MD
2020 Recipient of the Gary S. Gilkeson Career Development Award
University Health Network (Toronto)
Title of Project: Interferon alfa as a Biomarker to Predict Lupus Nephritis Response to Treatment
Mentor: Murray Urowitz, MD, FRCPC Director, University of Toronto Lupus Clinic and Research Program Professor of Medicine, University of Toronto Senior Scientist, Krembil Research Institute
Project Summary: Kidney disease (LN) occurs in up to 65% of patients with SLE and is highly variable both in severity and response to therapy. Unfortunately, 30% of patients will not respond to treatment and develop impaired kidney function, with 15% requiring dialysis or transplantation. Achieving a complete response to treatment is critical for preserving long-term kidney function, but predicting who will respond to treatment is currently difficult.
There is therefore a need to develop new tests that will enable physicians to identify patients’ response to therapy early in the course so that appropriate therapy is provided.
Studies examining kidney biopsies, have found that patients who did not respond to therapy had higher levels of an inflammatory marker called type I interferon (IFN-1) induced genes in their kidney cells. suggesting that the measurement of IFN-I genes in the kidney could be used to predict treatment response, but this approach is invasive (requiring a biopsy) and expensive. IFN-I genes are induced by IFN-alpha and Neutrophil Extracellular Traps (NETs), two products of inflammatory cells, that can be measured in the blood.
Based on this knowledge, we hypothesize that the serum levels of IFN-alpha and/or NET complexes will help to identify responders from non-responders to conventional treatment in LN.
The aim of our study is to measure the blood levels of IFN-alpha and NET complexes at the time of a kidney flare in patients with LN and to determine whether the levels of these molecules can be used to predict the response to treatment.
The studied population will include 91 patients from The Lupus Clinic at Toronto Western Hospital and LuNNET cohorts and at least 10 from Dr. Dooley´s cohort, bringing the number of patients well over 100. All patients had a LN flare, 82 of which had kidney biopsy at the time of their flare (+/- 3 months). We will also include control populations, consisting of active SLE patients with no kidney disease during their flare and SLE patients who are inactive. All subjects have serum stored in biobanks from close to the time of the flare and have also been followed at least 2 years so we know which of them responded to treatment.
The proposed study could potentially improve renal outcomes by stratifying patients early in the disease course, differentiating those with a high probability of a poor prognosis, thus justifying a more aggressive therapy.