Overview
Complement component 3 glomerulopathy (C3G) is a rare and progressive form of glomerulonephritis characterized by dysregulation of the alternative complement pathway, primarily driven by uncontrolled activation of C3. This condition leads to immune complex deposition and subsequent renal damage, often resulting in proteinuria, hematuria, and progressive renal dysfunction. C3G predominantly affects adults but can occur in pediatric populations, with significant morbidity and potential for end-stage renal disease if left untreated. Early recognition and intervention are crucial in day-to-day practice to mitigate renal damage and preserve long-term kidney function 1.Pathophysiology
C3G arises from dysregulation of the alternative complement pathway, specifically due to mutations in genes encoding complement regulatory proteins such as CFHR1, CFHR3, CFHR4, C3, and C3 factor H-related proteins (CFHRs). These genetic alterations impair the ability of complement regulatory proteins to control C3 convertase activity, leading to excessive C3 activation and deposition in the glomeruli. The uncontrolled C3 activation results in the formation of immune complexes and subsequent inflammation, causing characteristic histological features like dense deposits of C3 along the glomerular basement membrane and mesangial areas. Over time, this chronic inflammation and immune complex deposition lead to glomerulosclerosis, tubulointerstitial fibrosis, and ultimately, renal failure 1.Epidemiology
The exact incidence and prevalence of C3G remain uncertain due to its rarity and diagnostic challenges. However, it is considered a relatively uncommon cause of glomerulonephritis, accounting for approximately 5-10% of primary glomerulopathies. C3G can affect individuals of any age but is more frequently diagnosed in adults, particularly those in their third to sixth decades. There is no clear sex predilection noted in most studies. Geographic distribution does not appear to show significant variations, though specific genetic predispositions might influence prevalence in certain populations. Trends over time suggest an increasing awareness and diagnostic capability rather than a true increase in incidence 1.Clinical Presentation
Patients with C3G typically present with a constellation of symptoms reflecting renal involvement, including hematuria, proteinuria (often in nephrotic range), and hypertension. Additional manifestations can include edema, particularly periorbital and generalized, and varying degrees of renal function impairment, ranging from mild proteinuria to acute kidney injury. Extra-renal manifestations are less common but can include systemic symptoms such as fatigue and arthralgias. Atypical presentations, such as those involving the eye (e.g., hypertensive retinopathy and Purtscher-like retinopathy), as seen in the reported pediatric case, highlight the multisystem involvement that can occur 1. Red-flag features include rapid decline in renal function, severe hypertension, and significant proteinuria, necessitating prompt diagnostic evaluation.Diagnosis
The diagnosis of C3G involves a comprehensive approach combining clinical evaluation, laboratory tests, and renal biopsy findings. Initial steps include assessing proteinuria, serum creatinine, and blood pressure levels. Renal biopsy is definitive, revealing characteristic dense C3 deposits along the glomerular basement membrane without significant immunoglobulin or complement C4 deposits, distinguishing it from other glomerulopathies. Specific diagnostic criteria include:Differential Diagnosis:
Management
First-Line Treatment
Plasma Exchange (PE):Immunosuppressive Therapy:
Second-Line Treatment
Rituximab:Refractory or Specialist Escalation
Eculizumab:Contraindications:
Complications
Acute Complications:Long-Term Complications:
Prognosis & Follow-Up
The prognosis of C3G varies widely depending on the severity of renal involvement at diagnosis and response to treatment. Early intervention with immunosuppressive therapy can stabilize or even improve renal function in some patients. Prognostic indicators include initial renal function, degree of proteinuria, and response to initial treatment. Recommended follow-up intervals typically include:Special Populations
Pediatrics
C3G in children, as exemplified by the reported case, can present with atypical manifestations such as retinopathy alongside renal symptoms. Early diagnosis and tailored immunosuppressive therapy are crucial, with careful monitoring of growth and development alongside renal function 1.Elderly
In elderly patients, comorbidities and polypharmacy complicate management. Close attention to drug interactions and renal dosing adjustments is essential. The risk of infections and cardiovascular complications is heightened, necessitating vigilant monitoring and supportive care 1.Key Recommendations
References
1 Shekarchian F, Hosseini SM, Khazaei S. Hypertensive retinopathy and Purtscher-like retinopathy in a child with complement 3 glomerulopathy. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus 2023. link