MICA Investigating the role of cytomegalovirus reactivation in amplifying monocyte driven renal damage in active ANCA associated vasculitis
Lead Research Organisation:
University of Birmingham
Department Name: Institute of Immunology & Immunotherapy
Abstract
In ANCA-associated vasculitis (AAV), the body's own white blood cells attack blood vessels. The kidneys are most commonly involved in AAV, frequently leading to kidney failure and dialysis. Amongst people that require dialysis, 2-3 out of 10 do not survive, and 4 out of 10 do not recover kidney function. Importantly, infection and heart disease are leading causes of death. Without treatment AAV is life-threatening; treatment involves powerful immunosuppression. Whilst prognosis has significantly improved, there remains significant risk of damage from the disease and its treatment, especially during the first 12 months.
Cytomegalovirus (CMV) is a common virus, present in over half the population. After initial infection, the virus remains in the body for life and undergoes periods of reactivation. In a healthy person, the immune system keeps the virus under control. Recent research within my supervisors' group, showed that asymptomatic CMV reactivation occurs in roughly 1 in 4 people with stable AAV and leads to expansions of harmful immune cells able to damage blood vessels. We know that CMV reactivation and expansion of these harmful cells are associated with reduced kidney function and increased risk of infection and heart disease.
What we do not yet know is how often asymptomatic CMV reactivation occurs in patients with newly diagnosed or recently relapsed AAV. We anticipate that CMV will reactivate much more frequently during the first 12 months following diagnosis or relapse (the acute phase), due to the medication needed to suppress the immune system and inflammation from the vasculitis, and that this will be linked with worse outcomes.
We also do not yet know how CMV reactivation may amplify the damage that vasculitis can do to the kidney. Our preliminary work suggests that CMV reactivation increases the proportion of a specific inflammatory group of white blood cells called monocytes (CCR2 expressing monocytes) in AAV. Our preliminary findings suggest that in these patients, the more CCR2 expressing monocytes in the blood, the worse the kidney function. There is also an increasing amount of evidence now that blocking CCR2 monocytes in mice reduces kidney damage across a wide variety of kidney conditions. This suggests that this monocyte-induced kidney damage pathway is not just limited to patients with vasculitis.
The main aims of this study are to measure the frequency of CMV reactivation during the first 12 months and determine whether this is linked to increased disease activity, ongoing dialysis requirement and increased damage from AAV. We will then explore whether CMV reactivation causes an increase in CCR2 expressing monocytes, and whether these monocytes cause persistent kidney damage in AAV.
We will aim to recruit all patients with newly diagnosed or recently relapsed AAV. Patients will be followed up with 10 study visits over 12 months. At each visit, participants will be required to give blood and urine samples to determine if CMV has reactivated and measure other inflammatory chemicals and proteins. Participants will also be asked to fill in a questionnaire on their health and quality of life. A kidney biopsy is performed routinely to confirm a diagnosis of AAV. We will use some of this kidney tissue to identify the number of monocytes in the tissue and assess if this is related to the kidney damage we see on the biopsy.
If our current proposed study confirms that CMV reactivation is common during acute AAV and is linked with significant complications, this may lead to future research of suppression of CMV in a trial, aiming to improve outcomes for people with AAV. This research will also improve our understanding of the importance of CMV in driving kidney damage which may be relevant to other kidney conditions.
Cytomegalovirus (CMV) is a common virus, present in over half the population. After initial infection, the virus remains in the body for life and undergoes periods of reactivation. In a healthy person, the immune system keeps the virus under control. Recent research within my supervisors' group, showed that asymptomatic CMV reactivation occurs in roughly 1 in 4 people with stable AAV and leads to expansions of harmful immune cells able to damage blood vessels. We know that CMV reactivation and expansion of these harmful cells are associated with reduced kidney function and increased risk of infection and heart disease.
What we do not yet know is how often asymptomatic CMV reactivation occurs in patients with newly diagnosed or recently relapsed AAV. We anticipate that CMV will reactivate much more frequently during the first 12 months following diagnosis or relapse (the acute phase), due to the medication needed to suppress the immune system and inflammation from the vasculitis, and that this will be linked with worse outcomes.
We also do not yet know how CMV reactivation may amplify the damage that vasculitis can do to the kidney. Our preliminary work suggests that CMV reactivation increases the proportion of a specific inflammatory group of white blood cells called monocytes (CCR2 expressing monocytes) in AAV. Our preliminary findings suggest that in these patients, the more CCR2 expressing monocytes in the blood, the worse the kidney function. There is also an increasing amount of evidence now that blocking CCR2 monocytes in mice reduces kidney damage across a wide variety of kidney conditions. This suggests that this monocyte-induced kidney damage pathway is not just limited to patients with vasculitis.
The main aims of this study are to measure the frequency of CMV reactivation during the first 12 months and determine whether this is linked to increased disease activity, ongoing dialysis requirement and increased damage from AAV. We will then explore whether CMV reactivation causes an increase in CCR2 expressing monocytes, and whether these monocytes cause persistent kidney damage in AAV.
We will aim to recruit all patients with newly diagnosed or recently relapsed AAV. Patients will be followed up with 10 study visits over 12 months. At each visit, participants will be required to give blood and urine samples to determine if CMV has reactivated and measure other inflammatory chemicals and proteins. Participants will also be asked to fill in a questionnaire on their health and quality of life. A kidney biopsy is performed routinely to confirm a diagnosis of AAV. We will use some of this kidney tissue to identify the number of monocytes in the tissue and assess if this is related to the kidney damage we see on the biopsy.
If our current proposed study confirms that CMV reactivation is common during acute AAV and is linked with significant complications, this may lead to future research of suppression of CMV in a trial, aiming to improve outcomes for people with AAV. This research will also improve our understanding of the importance of CMV in driving kidney damage which may be relevant to other kidney conditions.
Technical Summary
Mortality from AAV remains 2.6 times worse than the healthy population and is highest during the first 12 months. Our group have already demonstrated that subclinical CMV reactivation in patients with AAV in remission is common and is associated with adverse outcomes, including reduced kidney function and increased mortality. I hypothesise that subclinical CMV reactivation will be more frequent in patients with active disease leading to worse disease outcomes.
In this observational study, I will recruit patients with AAV within 14 days of disease presentation or relapse, to determine the proportion of patients with CMV reactivation on quantitative PCR assessment of blood or urine samples collected at each study visit over 12 months follow up. I will determine whether CMV reactivation is associated with adverse patient outcomes including renal function, proteinuria, disease activity and damage.
I will also investigate whether subclinical CMV reactivation leads to persistent kidney injury through the expansion of pro-inflammatory CCR2 expressing monocytes. This will be achieved using flow cytometry to characterise the local and systemic monocytic repertoire in relation to CMV reactivation. The profile and number of virally infected CCR2+ monocytes will then be compared to episodes of CMV reactivation, to determine whether repeated rounds of CMV reactivation drives expansion of this cell subset. I will then assess potential mechanisms of renal damage induced by CCR2+ monocytes using NanoString technology and biopsy imaging software. I will perform in-vitro add-back experiments to determine whether CCR2+ are capable of damaging glomerular endothelium.
If CMV reactivation occurs frequently and associates with adverse outcomes, this study's results will inform the design of a clinical trial of CMV suppression. This research will also improve our understanding of monocyte driven renal damage relevant to AAV but also other inflammatory renal conditions
In this observational study, I will recruit patients with AAV within 14 days of disease presentation or relapse, to determine the proportion of patients with CMV reactivation on quantitative PCR assessment of blood or urine samples collected at each study visit over 12 months follow up. I will determine whether CMV reactivation is associated with adverse patient outcomes including renal function, proteinuria, disease activity and damage.
I will also investigate whether subclinical CMV reactivation leads to persistent kidney injury through the expansion of pro-inflammatory CCR2 expressing monocytes. This will be achieved using flow cytometry to characterise the local and systemic monocytic repertoire in relation to CMV reactivation. The profile and number of virally infected CCR2+ monocytes will then be compared to episodes of CMV reactivation, to determine whether repeated rounds of CMV reactivation drives expansion of this cell subset. I will then assess potential mechanisms of renal damage induced by CCR2+ monocytes using NanoString technology and biopsy imaging software. I will perform in-vitro add-back experiments to determine whether CCR2+ are capable of damaging glomerular endothelium.
If CMV reactivation occurs frequently and associates with adverse outcomes, this study's results will inform the design of a clinical trial of CMV suppression. This research will also improve our understanding of monocyte driven renal damage relevant to AAV but also other inflammatory renal conditions
