Ana Konvalinka

Administrative Assistant: Ms. Guilhermina Markopoulos, Guilhermina.Markopoulos@uhn.ca, 416-340-4800 x 6950

Research Synopsis

Over 10% of the world population has chronic kidney disease (CKD). Patients with CKD have mortality rates that are comparable to that of cancer. These patients develop kidney fibrosis, leading to kidney failure requiring dialysis or a kidney transplant. Patients with kidney failure can continue to experience problems with rejection and fibrosis after a kidney transplant. The focus of my research program is to identify novel mechanisms and treatments for kidney fibrosis and rejection with the goal of extending the longevity of transplanted kidneys and slowing progression of native kidney disease.

My lab has collaborative and interdisciplinary projects, that utilize novel methods and systems biology approaches to study the following themes:
1. Fibrosis
2. Antibody-mediated rejection
3. Ischemia reperfusion injury
4. Biology of sex differences in kidney disease
Fibrosis: Native and allograft kidney fibrosis represents the final common process of organ failure, with no effective therapy. The development of novel therapies has been hampered, at least in part, by the lack of early, non-invasive markers of fibrosis. We have identified a group of proteins regulated by a fibrogenic stimulus, angiotensin II, in kidney cells and demonstrated that these proteins were involved in kidney fibrosis in vivo. Urine measurements of these proteins correlate with kidney allograft fibrosis in kidney transplant recipients. Interestingly, these proteins can also be measured in bronchoalveolar lavage of the lung transplant patients and predict the development of lung fibrosis. We are currently studying the mechanisms of regulation of these fibrosis signature proteins. Agents that inhibit these proteins may represent new potential treatments for kidney disease.
Antibody Mediated Rejection: AMR is the leading cause of premature kidney allograft loss. Pathophysiology of AMR is incompletely understood and therapeutic options are limited. This type of rejection is linked to antibodies directed against the donor graft, however, not all antibodies lead to graft injury. What remains unclear is how early kidney AMR is initiated and perpetuated by the antibodies. We are utilizing systems biology and proteomics approaches to identify compartment-specific proteome changes in AMR and antibodies more likely to cause graft injury. We are also utilizing single cell analyses of kidney allograft biopsies to understand the interactions between immune and parenchymal cells in the kidney microenvironment. Finally, we are examining glycan modifications on donor-specific antibodies in AMR, to establish if they are important determinants of injury. We aim to identify new therapeutic targets for AMR.
Ischemia Reperfusion Injury: Ischemia-reperfusion injury is an important reason for kidney fibrosis that is sustained at the time of transplantation. We studied the proteome of pig kidneys subjected to normothermic ex vivo perfusion (NEVKP) to better understand why this method of kidney preservation protects the grafts from injury. We discovered mitochondrial protein preservation during NEVKP. These proteins may protect kidneys by preserving metabolism, and represent the targets of potential therapies that could be delivered to the kidney prior to transplant.
Biology of Sex Differences: Male sex is associated with increased risk of CKD progression, but the mechanisms that explain this are poorly understood. We demonstrated, for the first time, that male and female kidney cells metabolize glucose and glutamine differently, with male cells showing accentuated injury. In large international cohorts of patients with and without diabetes, and with and without CKD, we showed that these metabolic differences in cells are evident in the blood metabolites of males and females, and that metabolites involved in the mitochondrial TCA cycle are higher in males and positively correlated with mortality. Our findings may influence how we assess and treat women and men with kidney disease.