Clinical Guidance

To date, the most striking genotype-phenotype correlation has been with CFHR fusion genes and the C3GN phenotype (as opposed to the DDD phenotype) .

Source: GeneReviews — "C3 Glomerulopathy"

Diagnostic Criteria

C3 glomerulopathy (C3G) is a complex ultra-rare complement-mediated renal disease caused by uncontrolled activation of the complement alternative pathway (AP) in the fluid phase (as opposed to cell surface); it is rarely inherited in a simple mendelian fashion.

Suggestive Findings

C3G should be suspected in individuals of all ages who present with one of the following:

• Hematuria

• Proteinuria

• Hematuria and proteinuria

• Acute nephritic syndrome

• Nephrotic syndrome

• Persistent hypocomplementemia (low serum levels of complement component C3)

Establishing the Diagnosis

The diagnosis of C3G is established in a proband with typical findings on renal biopsy. Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes listed in...

Source: GeneReviews — "C3 Glomerulopathy"

Differential Diagnosis

Table 3. Disorders to Consider in the Differential Diagnosis of C3G

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with C3G, the following evaluations are recommended if they have not already been completed:

• Evaluate the complement system by measuring serum/plasma concentrations of C3, C3c, C3d, C4, C5, fB, Ba, Bb, fH, fI, properdin, and s(C5b-9).

• Quantitate the degree of complement function by measuring CH50 and APH50.

• Measure autoantibodies including C3NeFs, C4NeFs, C5NeFs, FHAA, and FBAA.

• Establish the extent of renal disease by measuring serum creatinine concentration, and monitor creatinine clearance, proteinuria, and hematuria.

• Quantitate the degree of chronic renal damage by renal biopsy.

• Obtain a baseline ophthalmologic examination.

• Consult with a clinical geneticist and/or genetic counselor.

Treatment of Manifestations

Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G. Nonspecific therapies are most commonly used. Nonspecific therapies have been shown to be effective in numerous chronic glomerular diseases. The judicious use of these agents along with optimal blood pressure control is of benefit in individuals with C3G.

Source: GeneReviews — "C3 Glomerulopathy"

Therapies Under Investigation

Numerous anti-complement therapies are entering clinical trials for individuals with C3G. These trials are registered under ClinicalTrials.gov. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "C3 Glomerulopathy"

Surveillance Guidelines

The following are appropriate:

• Close monitoring of renal function by a nephrologist with familiarity with the C3G disease spectrum

Note: Frequency of follow up and testing required is determined by the degree of renal dysfunction.

• Complete biannual assessment of the complement pathway

• Periodic eye examinations to evaluate the fundus

Source: GeneReviews — "C3 Glomerulopathy"