Natural History Study of C3 Glomerulopathy
Research type
Research Study
Full title
Natural History Study of C3 Glomerulopathy: Discovery of Histological Predictors of Outcome
IRAS ID
213066
Contact name
Becky Ward
Contact email
Sponsor organisation
Imperial College London
Duration of Study in the UK
2 years, 11 months, 23 days
Research summary
Research Summary
C3 glomerulopathy (C3G) describes a rare renal disease characterised by the presence of C3 in the filtering units (glomeruli) in the kidney. C3 accumulation in the kidney results from over-activation of part of the immune system known as the complement alternative pathway. C3 accumulation results in inflammation in the glomeruli (glomerulonephritis) and this inflammation results in permanent damage in 30-50% of patients within 10 years of diagnosis, with these patients requiring dialysis or a transplant.
Currently there is no available cure for C3G and there is no approved treatment to prevent disease progression. Patients have a variable course of disease which is difficult to predict and treat. There is a need to understand better the clinical course of C3G, that is its natural history. Natural history refers to the clinical course of the condition in the setting of current standard of care. This includes supportive therapy (blood pressure control, anti-proteinuria agents) and in some individuals, immunosuppression.
The aim of this study is to determine the pathological spectrum of C3G, using clinical features available at diagnosis, including renal biopsy results, which will enable us to meaningfully stratify patients with C3G into different prognostic groups and/or treatment groups. We aim to determine precise histological and clinical indicators and biomarkers of disease that my likely predict therapeutic response. This is extremely important to patients with C3G. In order to achieve this we aim to collect a large group of patients from different centres around the world.
We use the term C3 glomerulopathy to encompass all related complement-derived pathological sub-types: C3 glomerulonephritis, dense deposit disease, idiopathic membranoproliferative glomerulonephritis, atypical post-infectious glomerulonephritis, unspecified C3 glomerulopathySummary of Results
C3 glomerulopathy (C3G) and idiopathic immunoglobulin-associated membranoproliferative glomerulonephritis (Ig-MPGN) are kidney diseases characterised by abnormal presence of a protein called C3 in the filtering units (glomeruli) in the kidney. C3 accumulation results in inflammation in the glomeruli (glomerulonephritis) resulting in permanent damage in approximately 50% of patients within 10 years of diagnosis, with these patients requiring dialysis or a transplant.
Currently there is no available cure for C3G and although there are several drugs being tested in clinical trials, there is no approved treatment to prevent disease progression. Patients have a variable course of disease which is difficult to predict and treat. There is a need to understand the natural history of this disease. Natural history refers to the clinical course of the condition in the setting of current standard of care. This includes supportive therapy and immunosuppression.
The aim of this study was to determine the pathological spectrum of C3G, by performing a rigorous assessment of patient biopsies and by using clinical features available at diagnosis, enabling us to meaningfully stratify patients with C3G into different prognostic groups and/or treatment groups.
193 patients with C3G or Ig-MPGN, within the United Kingdom (UK) United States of America (USA) and Australia were recruited into the study. A total of 256 biopsies were scored, including 156 native kidney diagnostic biopsies, 60 repeat native kidney biopsies and 40 transplant kidney biopsies We performed a detailed analysis of scanned electronic slides of the renal biopsies and developed and validated a C3G specific histological scoring system. We then analysed the relationship between the histological scores, clinical parameters routinely measured in a patient’s course of disease (including estimated glomerular filtration rate; an estimation of how well kidneys are working, eGFR), proteinuria (protein in the urine; a marker of kidney damage), C3 level, C4 level, blood pressure, creatinine, albumin, medication, infection history), and patient outcome.
Frequent biopsy features identified were increase in cells in the glomeruli (termed mesangial expansion, mesangial hypercellularity and endocapillary hypercellularity; EH) and glomerular basement membrane (GBM) double contours. A multivariable analysis showed negative associations between eGFR, and crescents (pattern of acute or chronic, severe kidney injury), interstitial inflammation, and interstitial fibrosis and tubular atrophy (IFTA; marker of chronic injury). Proteinuria positively associated with endocapillary hypercellularity and GBM double contours. Analysis of repeat native biopsies did not demonstrate a relationship between immunosuppression treatment and improvement in histology features. Risk of progression to kidney failure was associated with eGFR and proteinuria at time of biopsy, and cellular/fibrocellular crescents, segmental sclerosis (scarring) and IFTA scores.
Our detailed assessment of kidney biopsies indicated that cellular/fibrocellular crescents and IFTA scores were significant determinants of deterioration in kidney function. These kidney biopsy features could be incorporated into clinical prediction models to enable patient stratification according to risk of progression. If validated, this approach is readily translatable to the clinic, and could be informative for stratifying patients for new therapies.REC name
West Midlands - Black Country Research Ethics Committee
REC reference
16/WM/0497
Date of REC Opinion
29 Nov 2016
REC opinion
Favourable Opinion