The main goal is to define whether macrophages from patients with AGN induce T-cell activation and migration due to their pro-inflammatory phenotype.
ID
Source
Brief title
Condition
- Autoimmune disorders
- Renal disorders (excl nephropathies)
- Vascular disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameters are mRNA and protein expression levels of
monocyte-derived macrophages in vitro and macrophages in situ in renal
biopsies, and activation and migration of T-cells which are co-cultured with
activated macrophages.
Secondary outcome
Secundary study parameters are T-cell receptor repertoires of migrated T-cells,
HLA-DPB1*04:01 status in AGN patients, quality of life (SF-36, patient
reported outcome measure, disease specific: AAV-PRO), fatigue levels (SF-36,
AAV-PRO)
Background summary
Anti-neutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis
(AGN) is a rare autoimmune disease which results in end-stage renal disease in
25% of patients despite improved treatment options over the last twenty years.
Even in periods with low disease activity, patients report a significantly
reduced quality of life and high levels of fatigue. The pathophysiology of AGN
remains enigmatic. The priming of neutrophils due to an unknown trigger is
considered crucial, which leads to T-cell recruitment and activation,
endothelial damage and vasculitis. Remarkably, in AGN, monocytes and
macrophages are always present in vasculitis and/or granulomatous lesions. It
is unknown whether macrophages attempt to repair or cause damage in AGN.
Preliminary data showed that CXCL10, an important chemokine attracting T-cells,
is increased in monocyte-derived macrophages from AGN patients. These findings
and the abundant presence of macrophages in tissue lesions, indicate a central
pro-inflammatory role for macrophages in AGN. This study aims to investigate
whether macrophages play a central role in AGN, continuously activating the
immune system, as opposed to the long-held belief that neutrophils do so. Our
hypothesis is that macrophages drive ANCA glomerulonephritis by activating
T-cells and enhancing their migration towards vasculitic inflammation.
Permanent macrophage activation could contribute to chronic elevation of
fatigue levels.
Study objective
The main goal is to define whether macrophages from patients with AGN induce
T-cell activation and migration due to their pro-inflammatory phenotype.
Study design
This study is designed as a multi-center observational study with longitudinal
follow-up. Patients will be asked to have their blood drawn, to sample urine
and fill out quality of life questionnaires. Next, in vitro monocyte-derived
macrophage phenotype will be assessed by bulk RNA sequencing and macrophage
induced T-cell activation and migration will be measured by a 3D system and a
leucocyte extravasation essay. Macrophage phenotype in situ will be assessed by
immunohistochemistry and immunofluorescence in renal biopsies (available for
initial diagnosis) and by single-cell RNA sequencing of a small number (n=8) of
fresh kidney biopsies derived from AGN patients and systemic lupus
erythematosus (SLE) patients with renal involvement (n=3) who undergo a renal
biopsy for diagnostic purposes. Surplus *healthy* kidney tissue derived from
patients who undergo a (partial) nephrectomy for a renal cell carcinoma (n=3)
will be used as control tissue for single-cell sequencing experiments.
Study burden and risks
There is no individual benefit from participation in this study. This study
will increase knowledge about the etiology of ANCA vasculitis and may
ultimately provide a target for new treatment options in the future. Minimal
burden and risks are associated with participation. Patients who undergo an
extra biopsy during a diagnostic renal biopsy, do not experience increased risk
of adverse events as the maximum number of passes will be set at 3 biopsies.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet
following general and group-specific criteria:
General
1. Age: 18 years and older
Group-specific
Patients with ANCA-associated glomerulonephritis (AGN)
1. Diagnosed with granulomatosis with polyangiitis (GPA) or microscopic
polyangiitis (MPA)
2. Renal involvement attributable to vasculitis
3. History of PR3/MPO positivity as determined by ELISA in the context of
routine clinical care.
Hemodialysis controls
1. End stage kidney failure (ESRD) requiring hemodialysis
Active infection controls
1. Clinical diagnosis: pneumonia (CURB-65 score 2-5, imaging: X-thorax or
CT-thorax showing infiltrates) or complicated urine tract infection
2. Admitted to the hospital <48h
Nephrectomy controls
1. Patients who undergo a (partial) nephrectomy for treatment of a renal cell
carcinoma, who give consent for the use of surplus kidney tissue for research
purposes
Patients with (suspected) ANCA vasculitis with pulmonary involvement (API)
1. Suspected or diagnosed with ANCA-associated vasculitis
2. (Suspected) pulmonary involvement attributable to vasculitis
3. Patients who undergo a bronchoalveolar lavage (BAL) for diagnostic purposes
SLE patients with renal involvement
1. SLE diagnosis according to the 2019 EULAR/ACR Classification Criteria18
2. Renal involvement attributable to SLE
3. History of ANA positivity
Exclusion criteria
Patients with ANCA-associated glomerulonephritis (AGN) and Patients with
(suspected) ANCA vasculitis with pulmonary involvement
1. A history of drug-induced ANCA-associated vasculitis
2. Active infection as shown by microbiological analysis
Healthy controls and hemodialysis controls
1. Active infection as shown by microbiological analysis
2. A history of any auto-immune disease
3. Use of immunosuppressive medication
Infection controls
1. Other infection than pneumonia/urine tract infection
2. A history of any auto-immune disease
3. Use of immunosuppressive medication
SLE patients
1. A history of drug-induced SLE
2. Active infection as shown by microbiological analysis
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL74517.018.20 |
| OMON | NL-OMON29001 |