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Overlap of C3 Glomerulopathy and Thrombotic Microangiopathy: A Case Series
Aishwarya Ravindran1,2, Lilian Monteiro Pereira Palma3, Fernando C Fervenza4
1Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Insights
Dysregulation of the alternative complement pathway can cause both C3 glomerulopathy (C3G) and thrombotic microangiopathy (TMA). This study examines five patients with overlapping C3G and TMA, highlighting rare clinical presentations and outcomes.
Area of Science:
- Nephrology
- Complement System
- Pathology
Background:
- Alternative complement pathway dysregulation is implicated in C3 glomerulopathy (C3G) and thrombotic microangiopathy (TMA).
- Concurrent C3G and TMA is a rare clinical entity.
Purpose of the Study:
- To describe the clinical, pathological, and genetic findings in patients with co-occurring C3G and TMA.
- To characterize the phenotypes and outcomes of this rare overlap syndrome.
Main Methods:
- Retrospective review of 114 patients with C3G from 2007-2016.
- Inclusion of patients with concurrent TMA based on native kidney biopsy findings.
- Analysis of clinical presentation, immunofluorescence, electron microscopy, and complement studies.
Main Results:
- Five patients with overlapping C3G and TMA were identified.
- Patients presented with either C3G-predominant or TMA-predominant phenotypes.
- Pathogenic complement gene mutations or autoantibodies were identified in some cases, with one patient having monoclonal gammopathy.
Conclusions:
- Overlap of C3G and TMA is rare and presents with distinct phenotypes.
- Further research is needed to understand the long-term renal survival implications of concurrent C3G/TMA.
Introduction:
Dysregulation of alternative complement pathway underlies the pathogenesis of both C3 glomerulopathy (C3G) and thrombotic microangiopathy (TMA). In this study, we describe both disease entities occurring in 5 patients.
Methods:
We identified 114 patients at our institution from 2007 to 2016 with C3G in native kidney biopsies and those with concurrent TMA were included.
Results:
The median age at diagnosis was 58 years (range: 28-69); all were male. Median serum creatinine and proteinuria at presentation were 2.3 mg/dl and 2089 mg/d, respectively. Three cases presented with TMA-predominant phenotype and 2 with C3G-predominant phenotype. Immunofluorescence (IF) showed bright C3 staining in mesangium and/or capillary walls. Electron microscopy showed marked subendothelial expansion by fluffy material in the capillary loops without associated deposits. However, capillary wall deposits were present in other loops in 4 cases. Mesangial deposits were present in all cases. Four cases showed low C3, of which 2 showed low C4. Complement evaluation in 3 cases showed pathogenic CFH mutation in 1 case, and multiple variant of unknown significance along with factor B autoantibody and C4 nephritic factor in 1 case. One patient negative for complement abnormalities had a monoclonal gammopathy. Three cases were treated with steroids and/or immunosuppressants. One case progressed to end-stage renal disease (ESRD) at 38.3 months; the remaining showed median serum creatinine and proteinuria of 2.5 mg/dl and 1169 mg/d, respectively at median follow-up of 17.5 months.
Conclusion:
Overlap of C3G and TMA is rare and can clinically present as C3G-predominant or TMA-predominant phenotype. The significance of concurrent C3G/TMA findings on long-term renal survival remains to be explored.
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