Background: C3 glomerulopathy (C3G) encompasses a group of diseases that result from abnormalities in the alternative pathway of complement regulation, and has been defined by C3 only or C3-dominant immunofluorescence staining seen on renal biopsy. C3G includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD); the latter of which is characterized ultra-structurally by the presence of highly osmiophilic intramembranous deposits. Both C3GN and DDD often present with a membranoproliferative pattern of glomerular injury, a finding that can also be seen in thrombotic microangiopathy (TMA). Most common causes include infection, autoimmune and monoclonal gammopathy.
Case presentation: A 70-year-old man with hypertension, prediabetes, obesity, and stage 4 chronic kidney disease presented with headache and generalized weakness and was found to have a blood pressure of 250/118 mmHg, consistent with hypertensive emergency. One week earlier, he had been treated with corticosteroids for a generalized rash. Despite blood pressure stabilization, he developed rapidly progressive renal failure requiring intensive care admission, intubation, and renal replacement therapy. Renal biopsy demonstrated dominant C3 deposition (3+) with coarse granular staining along glomerular capillary loops and mesangium, consistent with C3-dominant glomerulonephritis. Complment C3 was 19, rest unremarkable. Autoimmune, infectious, and monoclonal gammopathy evaluations were negative. He was discharged on optimized antihypertensive therapy. He had repeat admission for generalized maculopapular rash. currently managed with immunosuppression with plans for complement-directed therapy.
Lesson learned: C3Gn can masked with underlying kidney disease. Renal biopsy is main diagnostic tool. In addition, immunological/biochemical evidence of complement involvement should be sought by measuring plasma levels of C3, C4, FH, FI, FB, and soluble C5b9 complexes, and by screening autoantibodies (anti-FH, anti-FB, C3Nef, C4Nef, C5Nef). There is great interest and an apparently increasing role of complement inhibition (i.e., off-label utilization of C5 convertase inhibitors such as eculizumab or other novel complement blocking agents like iptacopan). Many patients will be dialysis dependent in 5-year period, suggesting poor prognosis despite optimal treatment.
Conclusion: C3-dominant glomerulonephritis may present as hypertensive emergency and be masked by underlying chronic kidney disease. Early renal biopsy and complement evaluation are critical to guide prognosis and emerging complement-targeted therapy.