C3 Glomerulopathy Diagnosis

C3 glomerulopathy (C3G) is a group of kidney diseases caused by dysregulation of the alternative complement pathway, resulting in abnormal deposition of complement protein C3 within the glomeruli and renal dysfunction. The prevalence of C3G is estimated to be around 5 cases per 1,000,000 persons.^[1] Arnold B. Alper, Jr, MD, MPH, an associate professor at Tulane University School of Medicine, New Orleans, Louisiana, talked to Medscape about the challenges in C3G diagnosis.

C3G is considered a rare disease. What signs and symptoms should prompt clinical suspicion?

C3G is a rare disease with a variable presentation. We don't have huge patient numbers to learn from, so this diagnostic hypothesis might not be the first thing that comes to mind. Patients with C3G typically present with mild to severe proteinuria — 500 mg to > 3 or 4 g — and hematuria. Along with proteinuria and hematuria, varying degrees of renal insufficiency are commonly observed. Patients often report a history of hypertension, and in some cases, C3G is preceded by an upper respiratory tract infection, especially in children and young adults.^[2] You would probably be considering other more common diagnoses, such as postinfection glomerulonephritis or lupus nephritis, depending on the patient's characteristics, so further investigation is necessary. The presence of low serum C3 levels is a potential clue for C3G.

Which laboratory investigations are recommended?

Given the role of complement dysregulation in C3G, serum complement measurement (C3 and C4) is crucial. As I mentioned, patients with C3G often present with low serum C3 levels. Typically, we assess kidney function and electrolyte levels and investigate other causes of glomerular disease, including autoimmune markers such as antinuclear antibody (ANA) and anti-neutrophil cytoplasmic antibody (ANCA), and hepatitis screening. Older patients should be screened for monoclonal gammopathy — another cause of C3 deposition — by serum protein electrophoresis immunofixation and serum free light chain evaluation. C3G diagnosis is confirmed by kidney biopsy.^[2]

Is disease progression an indication for biopsy?

Yes, disease progression — decreased renal function, increased proteinuria, and persistent hematuria — is an indication for kidney biopsy in suspected C3G cases. Kidney biopsy is necessary for definitive diagnosis, and it can also serve to monitor disease progression and guide treatment decisions. Light microscopy findings are similar to those in other forms of glomerulonephritis, including mesangial and endocapillary proliferative lesions and crescentic and membranoproliferative lesions. Immunofluorescence staining for C3 will show glomerular C3 deposition without other immunoglobulin deposits.^[3] Genetic testing should be considered for patients with confirmed C3G diagnosis; approximately 20% of patients with C3G have a genetic variant in the genes encoding complement factors, such as CFB, CFH, and CFI.

New therapeutic options targeting complement activity have been approved by the US Food and Drug Administration. Which are the treatment options for patients with C3G?

Patient management strategies include supportive treatment, immunosuppressive agents, and anticomplement therapies. Blood pressure control with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is recommended in all patients.^[2] Clinicians could also consider introducing sodium-glucose cotransporter 2 inhibitors. Immunosuppressive treatment includes prednisone and mycophenolate mofetil for 3-6 months. Kidney function should stabilize or improve. If the disease progresses despite these interventions — proteinuria > 2000 mg/24 h or an increased serum creatinine level — then complement inhibitors could be considered, such as eculizumab or ravulizumab. We are still gathering more information about the use of complement inhibitors in rapidly progressive C3G. New promising therapies for C3G targeting complement activity include pegcetacoplan (a targeted C3 and C3b inhibitor) and iptacopan (a factor B inhibitor).^[4,5]

Editor's Note: This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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Cite this: C3 Glomerulopathy Diagnosis - Medscape - May 09, 2024.