C3 glomerulopathy (ORPHA:329918)
A form of primary membranoproliferative glomerulonephritis characterized by the presence in renal biopsy samples of a glomerulonephritis with sole (or at least dominant) glomerular immunofluorescence staining for C3. Non-specific alterations or proliferative patterns with C3-dominant glomerular staining are also possible. Based upon electron microscopic findings, C3 glomerulopathy (C3G) may be further classified as C3 glomerulonephritis (C3GN) or Dense deposit disease (DDD).
Epidemiology
The estimated incidence of CG3 is 1/300,000-1,000,000. C3G appears to affect both genders equally.
Clinical description
Features of DDD tend to appear earlier than those of C3GN, usually in adolescence. However, the signs and symptoms of either disease may not begin until adulthood. All patients with C3G have proteinuria and/or hematuria; proteinuria is variable and may be nephrotic range. Patients with C3G have variable degrees of azotemia at presentation and variable rate of kidney function decline. Hypertension may be present. Occasionally, rapidly progressive (crescentic) glomerulonephritis develops. Initial clinical manifestations of C3G may be preceded by upper respiratory tract infection. Many patients with DDD, and occasionally patients with C3GN, develop drusen in Bruch's membrane of the retina. Acquired partial lipodystrophy may be noted in DDD. Serum C3 levels are typically low in C3G and other complement abnormalities may be present (e.g. elevated serum levels of sC5b-9). Serum levels of classical pathway components are usually normal, although serum C4 levels may be low in a minority at some point in the disease course. C3 nephritic factor (C3NeF) is found in approximately 80% of patients with DDD and 40% of patients with C3GN.
Etiology
Whilst the pathophysiology is not fully elucidated, dysregulation of the alternative complement pathway is well documented: low serum C3 levels associated with C3NeF are observed in most patients and a few carry auto-antibodies against complement factor H (FH) or B (FB), or mutations in complement genes (including Complement Factor H Related genes (CFHR1, 2, 3, 5), CFH and C3). Mutations in combination with common susceptibility variants are also associated with an increased risk of C3G. In patients with underlying defects in the alternative complement pathway, C3G may be triggered by a common infection.
Diagnostic methods
The diagnosis of C3G is made by kidney biopsy in a patient with suspected glomerulonephritis, and is established on histopathology findings of C3 accumulation in renal tissue in the absence, or near-absence of immunoglobulin deposits. Electron microscopy is necessary to further categorized C3G into DDD and C3GN.
Differential diagnosis
The differential diagnosis includes almost all causes of acute glomerulonephritis and nephrotic syndrome in addition to atheroembolic disease, complement-mediated thrombotic microangiopathy and acute postinfectious glomerulonephritis.
Genetic counseling
Familial cases of C3G with a monogenic cause are rare. In sporadic cases, genetic variants are reported in about 20%, although the pathogenicity of these variants is unknown. When a variant is identified, genetic testing is recommended for family members.
Management and treatment
Currently, there are limited evidence-based guidelines to inform therapeutic decisions. General measures in all patients with C3G include blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, and treatment of dyslipidemia. As for those with primary C3G and nephritic-nephrotic phenotype, numerous therapeutic regimens have been tried, including the use of corticosteroids and immunosuppressants, plasmapheresis and plasma exchange. Various different treatment regimens have been reported (MMF and glucocorticoids, rituximab, and eculizumab) but the results are limited. In patients with evidence of alternative pathway of complement dysregulation, particularly if the above approach has not been successful, the use of complement inhibitory agents may be reasonable. Treatment with these agents, particularly with eculizumab, has only proven effective in approximately one-third of patients. Further agents acting upstream, at the C3 convertase level, need to be investigated in clinical trials.
Prognosis
Progression to end stage kidney disease occurs within 10 years of diagnosis in ~70% of affected children and 30-50% of affected adults. Disease recurrence in kidney transplants contributes to allograft loss in ~50% of patients within 10 years of transplantation.

                            Last update: 
                            August 2021


                            - Expert reviewer(s): 
                            Dr Erica DAINA | ERKNet* - Dr Marina VIVARELLI | ERKNet*


                                * European Reference Network