C3 Glomerulopathy

Etiology

Dysregulation of the alternative pathway can result from genetic mutations or the production of autoantibodies.

Genetic Mutations

Mutations involved are in the genes that encode for C3, complement factor B, factor H, factor I, and complement factor H-related protein 5.[2][3] About 25% of patients have detectable genetic mutations in these complement-related genes. However, due to the complexity of the complement system, few patients have relatives with the same disease.[4][5] Among patients diagnosed with familial C3G, C3GN is more common than DDD.[4]

Autoantibodies

Autoantibodies to various complement proteins stabilize the target complement proteins, increase their half-life, and prolong their activity.[2] C3 nephritic factor (CNeF) is the most common autoantibody known to cause C3G and does so by stabilizing C3 convertase (C3bBb), making it less susceptible to degradation by complement factor H and extending its biological activity.[6] Other autoantibodies include C5 nephritic factor against C5 convertase and autoantibodies against factor H and factor B. Paraproteinemias are thought to act as autoantibodies to C3 convertase or other regulating factors.[7]

Epidemiology

C3G is a rare condition; its incidence and prevalence are challenging to assess accurately. The best available information from registry data suggests that incidence and prevalence are approximately 1 to 3 cases per million and 5 cases per million, respectively, in the United States.[3] Patients with DDD tend to be younger than those with C3GN. Previously, DDD was considered a disease of children and young adults, but some series have also shown a prevalence in patients older than 60.[2][8] Both C3GN and DDD are most common in White patients and least common in Black patients.[9]

Pathophysiology

The complement system involves over 50 proteins and regulatory factors and can be cell-bound or soluble in the bloodstream. C3 is a common plasma protein in concentrations of up to 1.2 mg/mL, while factor H is the most common regulatory factor. Dysregulation of the alternative pathway underlies the development of C3G. Unlike the classical and lectin pathways of the complement system, the alternative pathway is constitutively active at a basal level, resulting from spontaneous hydrolysis of C3.

The basal activation of C3 is normally regulated by essential complement regulatory proteins, including factor H, factor H-related proteins, factor I, and membrane cofactor proteins. If left unchecked, activated C3 amplifies activation of the alternative pathway in a positive feedback loop, recruits inflammatory cells, and leads to membrane attack complex formation. Deposition of complement proteins in the glomerulus and tissue injury follows, leading to the histologic and clinical manifestations of C3G.[4] Dysregulation of the alternative pathway can result from genetic mutations, acquired autoantibody-related processes, or direct activation of the pathway via a systemic process, such as systemic lupus erythematosus, monoclonal gammopathy of undetermined significance, or monoclonal gammopathy of renal significance.[7] In the genetic form, gain-of-function mutations in complement-related proteins lead to overactivation of the alternative pathway.[2]

Histopathology

The diagnosis of C3G rests on biopsy findings characterized by glomerulonephritis with dominant C3 staining on immunofluorescence, as defined in the consensus report in 2013.[1] The report defined “dominant” as staining for C3 at least 2 orders of magnitude greater than any other immune reactants (ie, immunoglobulins, C1q, C4).[1][10] Light microscopy findings vary from normal morphology in rare cases to mesangial proliferative, membranoproliferative, and endocapillary proliferative with or without crescents.

Electron microscopy is essential to differentiate between DDD and C3GN. In DDD, electron microscopy reveals highly electron-dense deposits that appear sausage-like and are found within the lamina densa of the glomerular basement membrane, the mesangium, Bowman capsule, and the tubular basement membrane. These deposits are sometimes described as "ribbon-like."[4][8] In some cases, the deposits may involve the subendothelial and subepithelial regions of the glomerular basement membrane.

In C3GN, by contrast, deposits seen during electron microscopy are less dense, less organized, and are primarily in the mesangium and capillary walls.[7][11] In both DDD and C3GN, large subepithelial humps like those seen in infection-related glomerulonephritis (IRGN) may be found. In C3G, these subepithelial humps are composed of alternative complement pathway elements, while in infection-related glomerulonephritis, they are composed of immunoglobulins.[2][8]

History and Physical

The presentation of C3G varies from asymptomatic hematuria and proteinuria to symptoms of both nephritic and nephrotic syndrome. Microscopic hematuria, proteinuria, and hypertension are the most common presenting findings in patients with C3G.[3] Nephrotic syndrome is seen more frequently in C3GN than in DDD, while acute kidney injury is infrequent in C3GN and even rarer in DDD. In children and young adults, the diagnosis of C3G is often preceded by an upper respiratory infection, and older patients are more likely to have paraproteinemia.[4] Patients with monoclonal immunoglobulin G-related C3G are at a median age of 60 at diagnosis, compared to a median age of 28 in those with non-monoclonal immunoglobulin G-related C3G.[7]

Atypical hemolytic uremic syndrome with thrombotic microangiopathy lesions on histopathological examination is seen concurrently in fewer than 10% of patients with C3G.[12] Extrarenal manifestations, rare in C3G, are more common in concurrent C3G/atypical hemolytic uremic syndrome disease and include cutaneous and gastrointestinal symptoms. Patients with concurrent disease present with more severe acute kidney injury, although less severe than in atypical hemolytic uremic syndrome alone.[12]

Evaluation

C3G is a histopathologic diagnosis and requires a kidney biopsy. Please refer to the Histopathology section for a discussion of diagnostic findings. A kidney biopsy diagnostic of C3G should prompt a comprehensive investigation of the complement system's alternative pathway. While the availability of studies will be institution-dependent, the 2021 Kidney Disease Improving Global Outcomes guidelines recommend the following studies:

• Functional complement studies: hemolytic complement, CH50; alternative pathway, AP50; fumarate hydratase function
• Complement quantification: C3; complement component 4; factor I; factor H; factor B; properdin
• Complement activation: C3d; membrane attack complex; Bb
• Autoantibodies: anti-factor H; anti-factor B; nephritic factors

In patients who are found to have C3 nephritic factor, measurement of its capacity to stabilize C3 convertase should be attempted when possible.[3] Notably, only 50% to 70% of patients with C3G have low C3 levels, so normal levels do not rule out this disease.[5] For patients older than 50, an evaluation for dysproteinemia should be performed, including quantification of urine and serum free light chains and protein electrophoresis immunofixation, to establish the presence or absence of conditions such as multiple myeloma, Waldenström macroglobulinemia, amyloidosis or monoclonal gammopathy of renal significance. Paraproteins may act as a nephritic factor or an H autoantibody factor. A bone marrow biopsy may be warranted if other abnormalities are found.[2] Genetic testing for variants of complement genes, including C3, CFB, CFH, CFHR5, and CFI, should be considered when possible but remains challenging as these tests may not be readily available outside specialized laboratories.[3]

Treatment / Management

C3G treatment largely depends on disease severity at presentation after ruling out infection-related glomerulonephritis and in the absence of an underlying pathologic B-cell or plasma cell clone. Based on the degree of proteinuria and kidney function at diagnosis, C3G is classified into the following 3 categories:

• Mild disease (proteinuria <1 g/day and stable/normal kidney function)
• Moderate-severe disease (proteinuria >1 g/day or worsening renal function over a few months)
• C3G with a rapidly progressive glomerulonephritis presentation (crescent formation on kidney biopsy and rapid deterioration of kidney function) [13]

Supportive care, such as what is usually implemented for the management of patients with chronic kidney disease, is indicated for all the patients diagnosed with C3G regardless of disease severity and includes the following:

• Hypertension management
• Salt restriction
• Anti-proteinuric therapies like angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and sodium-glucose cotransporter 2 inhibitors
• Lipid-lowering therapy for hyperlipidemia
• Diuretics for edema, if needed

No single therapeutic regimen is universally effective for C3G. Patients with mild C3G can be treated with only supportive care and monitored over time. Immunosuppressive therapies are recommended for patients with moderate-severe C3G. If monoclonal gammopathy is present, treatment of the underlying disorder is warranted. Per 2021 Kidney Disease Improving Global Outcomes guidelines, in the absence of monoclonal gammopathy, a mycophenolate mofetil and steroid combination regimen is the first-line recommended treatment in the management of patients with moderate-to-severe C3G and is superior to other immunosuppressive agents in terms of remission induction and kidney survival.[13] Doses of mycophenolate mofetil (MMF) range from 750 to 1500 mg per day, with a mean of 1000 mg daily.[14] Pulse steroids can be considered for proteinuria in excess of 2 grams per day.[2] Eculizumab, a complement C5 inhibitor, is indicated in patients resistant to MMF and steroids or with findings concerning rapidly progressive disease.[15] Patients with a rapidly progressive glomerulonephritis presentation can be treated with a regimen composed of high-dose steroids in addition to either MMF or cyclophosphamide with or without eculizumab.[2][15](B3)

The VALIANT trial is a phase III trial evaluating the use of pegcetacoplan on C3 glomerulopathy. Preliminary data shows that pegcetacoplan, a C3/C3b inhibitor, is effective in reducing proteinuria in this condition.[16] The APPEAR-C3G trial is another phase III trial evaluating the effect of iptacopan on C3G in patients with biopsy-proven disease, including transplant patients. Iptacopan is an orally administered Factor B inhibitor that prevents the formation of C3 convertase, thereby inhibiting the alternative complement pathway. Currently used for paroxysmal nocturnal hemoglobinuria, it has also been tested for C3G and found to be effective in reducing C3 deposits in the disease.[17][18] Avacopan, a C5a receptor antagonist, is used as adjunctive therapy for ANCA-associated vasculitis. A randomized control trial showed no improvement in proteinuria or disease activity index when compared to placebo when used for C3G.[19] Plasma therapy and plasma exchange have also not yet proven effective, likely due to the reaccumulation of autoantibodies.[2](A1)

Patients who fail to respond to therapies are encouraged to enroll in clinical trials. Novel emerging therapies targeting various regulators of complement activation are being investigated in phase 2 and 3 clinical trials.[5] Some other agents studied have included danicopan, gene therapy, and stem cell treatment, but none of these have been proven effective at this time.[5][20][19][21](A1)

Differential Diagnosis

Diagnosis of C3G must include consideration of immune complex glomerulonephritis and infection-related glomerulonephritis (IRGN) in the differential diagnosis. Immunofluorescence studies on formalin-fixed, paraffin-embedded tissue can sometimes fail to detect immune complex glomerulonephritis, potentially leading to a misdiagnosis of C3G. This occurs because formalin can “mask” tissue antigens, interfering with their interaction with immunoglobulins and diminish their staining intensity. Immunofluorescence techniques such as using pronase, which helps “unmask” these antigens, have been developed to mitigate such diagnostic challenges.[22] In addition, using frozen tissue rather than formalin or paraffin-fixed tissue may be more accurate.[2]

In the case of IRGN, it is important to remember that C3-dominant immunofluorescence findings may represent late stages of IRGN, making it difficult to distinguish from C3G, warranting consideration in the differential diagnosis. The presence of subepithelial hump-shaped deposits commonly seen in IRGN is also a feature of C3G and insufficient to distinguish IRGN from C3G. The current consensus recommends monitoring these patients clinically and with laboratory tests. Patients with IRGN are expected to recover kidney function and resolve hypocomplementemia, proteinuria, and hematuria within 12 weeks.[3] If clinical and laboratory abnormalities persist beyond 12 weeks, C3G should be suspected, and a kidney biopsy should be performed to help differentiate between these 2 conditions.

Prognosis

Progression to end-stage kidney disease (ESKD) in cases of C3G occurs in up to 70% of children and 30% to 50% of adults within 10 years. In addition, the disease recurs in renal transplants and is responsible for graft loss in about 50% of cases.[2] Up to 50% of patients progress to ESKD in 5 years.[3][11] Multiple study results have identified clinical and histologic features associated with increased risk of progression. Features associated with a high risk of progression to ESKD include:

• Low baseline estimated glomerular filtration rate
• High level of proteinuria at baseline
• High chronicity score on biopsy
• Absence of immunosuppression therapy
• High stabilizing capacity of C3 nephritic factor [3][11]

In patients with ESKD secondary to C3G who receive a kidney transplant, the disease recurs in more than 50% of patients, often within the first year.[23] Disease recurrence is more frequent in DDD than in C3GN (80% vs 70%, respectively).[23]

Complications

Complications from C3G depend on the severity of the disease at presentation and its progression. Complications include:

• Risk of progression to chronic kidney disease and ESKD
• Complications of chronic kidney disease and ESKD: hypertension, increased cardiovascular risk, anemia, mineral bone disease
• Risk of nephrotic syndrome: dyslipidemia, volume overload, hypercoagulable state
• Complications and toxicity from immunosuppressive therapy
• Risk of opportunistic infections
• Risk of malignancy or infertility from cyclophosphamide
• Risk of steroid toxicity, including gastrointestinal, bone disease, glucose intolerance, volume overload, and hypertension
• Calcineurin inhibitor toxicity, including nephrotoxicity and neurotoxicity
• Mycophenolate mofetil side effects, including gastrointestinal, bone marrow suppression, teratogenicity
• Recurrence of disease post-transplant and subsequent burden of ESKD and dialysis-dependence
• Retinal complications in DDD, eg, drusen development