C3 glomerulopathy (C3G)

About C3 glomerulopathy

C3 glomerulopathy (C3G) is a rare and complex kidney disease that is primarily driven by dysregulation and excessive activation of the alternative complement pathway^1,2

C3G is characterised by dominant deposition of the complement component C3 in the renal glomeruli^2,3, resulting in chronic and irreversible kidney damage over time⁴ (Figure 1).

Figure 1. Complement system dysregulation in the pathophysiology of C3 glomerulopathy^1,3-8. C3, complement component 3; C5, complement component 5; C3G, C3 glomerulopathy; GBM, glomerular basement membrane.

C3G is rare, with a prevalence of around 0.2–5 cases per million in the US and Europe^4,9. It is most often diagnosed during childhood or young adulthood, and the median age at diagnosis is 22 years¹.

Treatment options for C3G are currently limited, and renal prognosis remains poor without disease-specific treatment options¹. Approximately 30–50% of patients with C3G progress to kidney failure within 10 years of diagnosis³. Almost all patients who undergo kidney transplantation experience disease recurrence, leading to renal allograft loss in up to 50% of patients within 10 years¹⁰.

Gain key insights from nephrologist Dr Carla Nester as she gives a brief overview of the current research being conducted into the causes of complement-mediated kidney diseases (CMKDs), including C3G and IgA nephropathy (IgAN).

Signs and symptoms of C3 glomerulopathy

C3G is a heterogeneous disease with variable clinical presentation⁴. Approximately one-third of adults with C3G present with acute kidney failure³.

The most common signs and symptoms of C3G are haematuria, proteinuria and nephrotic syndrome³. Others include:

• Signs of glomerulonephritis, often including hypertension^3,11
• Impaired kidney function³ and/or signs of acute and chronic kidney injury¹¹
• Low serum levels of C3 (most patients)^3,5
• Reduced estimated glomerular filtration³

Extrarenal manifestations in people with C3G may include premature onset of retinal drusen^12,13 and, rarely, acquired partial lipodystrophy^12,14.

Role of complement dysregulation in the pathophysiology of C3 glomerulopathy

Excessive activation of the alternative complement pathway¹⁵ is observed in the majority (>90%) of patients with C3G⁴ and is considered causal^1,5,15

For the remaining <10% of patients with C3G, complement dysregulation occurs in the classical and/or lectin pathways⁴.

The central pathological mechanism of C3G is C3 convertase overactivation¹, and dysregulation of the C5/C5 convertase axis has been implicated in disease severity and phenotype¹.

As a result of this complement dysregulation, continuous local complement activity leads to C3 deposition in the glomerulus, particularly C3b deposits in the glycocalyx^4,5. Complement deposition in the glomerulus has been associated with^4,6,16:

• activation and proliferation of endothelial and mesangial cells
• migration of immune cells to the glomerular compartment
• thickening of the glomerular basement membrane (GBM)
• podocyte dysfunction
• mesangial cell injury

This deposition can disrupt membrane function and trigger an inflammatory response, leading to glomerular damage⁵. Over time, inflammation and scarring can result in chronic and irreversible kidney damage⁴.

Causes of complement dysregulation in C3 glomerulopathy

Drivers of complement dysregulation in C3G can be acquired or genetic (Table 1)⁴.

Table 1. Acquired and genetic causes of complement dysregulation in C3 glomerulopathy^3,4,7,8. C3GN, C3 glomerulonephritis; C3Nefs, complement component 3 nephritic factor; C4Nefs, complement component 4 nephritic factors; C5Nefs, complement component 5 nephritic factors; CFHR1–CFHR5, complement factor H-related 1–5; DDD, dense deposit disease. *A specific gene-variant subtype of C3GN, CFHR5 nephropathy, is endemic to Cyprus (where it affects ~1 in 6,000 persons)³.

The most commonly detected drivers of complement dysregulation in C3G are autoantibodies to the C3 and C5 convertases, which disrupt regulation of normal convertase or protein function^3,4. Nephritic factors are autoantibodies commonly found in C3G that act to stabilise C3 or C5 convertases and prolong their half-life, leading to C3 or C5 consumption, respectively (Figure 2)^3,4.

Figure 2. Mechanism of action of nephritic factors on regulation of the complement pathway (Adapted¹⁷ under Creative Commons Attribution License (CC BY 4.0). Nephritic factors are autoantibodies commonly found in C3G³ that stabilise and prolong the half-life of C3 and/or C5 convertases^3,7,11, leading to chronic and unregulated complement activation in the fluid phase¹¹. (A) C3Nef binds to C3 convertase in the alternative pathway, which prevents its spontaneous Factor H-mediated decay¹⁷. (B) C5Nef binds to C5 convertase of the alternative pathway in the presence of properdin (P), which prevents its spontaneous and regulator-mediated decay¹⁷. (C/D) C4Nef binds to C3/C5 convertases in the classical/lectin pathway, which prevents their spontaneous, regulator-mediated decay¹⁷. Soluble and membrane regulators of the complement system are indicated in red boxes. CR1, complement receptor 1; C3Nef, C3 nephritic factors; C4BP, C4 binding protein; C4Nef, C4 nephritic factors; C5Nef, C5 nephritic factors; DAF, decay accelerating factor; FH, Factor H; FI, Factor I; MCP, membrane cofactor protein.

Overview of differential diagnosis for C3 glomerulopathy

Diagnosing C3 glomerulopathy (C3G) requires analysis of kidney biopsy tissue using light microscopy, immunofluorescence and electron microscopy². However, C3G is heterogenous in presentation and outcomes¹⁸, and its clinical presentation overlaps with a number of other glomerulopathies and C3-dominant kidney diseases^2,3.

Hear from Dr Carla Nester as she explains some of the key points to consider during differential diagnosis of C3G and related diseases.

For an overview of the steps involved in the differential diagnosis of C3G in practice, view our infographic below.

Overlap between C3 glomerulopathy and other conditions

Given the overlap in their clinical presentation and characteristics, differential diagnosis is required to distinguish between C3G and²:

• Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN, also known as immune complex glomerulonephritis¹⁹), including monoclonal gammopathy
• Post-infectious glomerulonephritis (PIGN)
• C4 glomerulopathy (C4G)
• Other conditions that result in an MPGN pattern of kidney injury, such as antiphospholipid syndrome and thrombotic microangiopathy

Initial workup based on clinical presentation

For patients presenting with signs and symptoms of C3G, initial workup and considerations for kidney biopsy are summarised in Table 2³.

Table 2. Initial workup based on clinical presentation and considerations for kidney biopsy^2,3.

Differential diagnosis based on kidney biopsy analysis

MPGN is the most commonly found lesion in C3G²⁰. For patients with this pattern of kidney injury, the following practice points from the 2021 KDIGO guidelines inform differential diagnosis^2,3.

A diagnosis of C3G is based on immunofluorescence analysis of a kidney biopsy specimen, which must demonstrate a dominant C3 deposition in the renal glomerulus (≥2 orders of magnitude greater than any other immune reactant)².

Before assigning a C3G diagnosis, other C3-dominant glomerular lesions should be excluded^2,3. These include PIGN and, for patients aged >50 years, monoclonal gammopathy ^2,3.

Once a diagnosis of C3G is confirmed, electron microscopy is used to determine the disease subgroup^2,3:

• Dense deposit disease (DDD) – defined by the presence of highly electron-dense, osmophilic, predominantly intramembranous deposits²
• C3 glomerulonephritis (C3GN) – involves mesangial and capillary wall deposits of lesser intensity²

Evaluations for complement dysregulation

Evaluations for complement dysregulation may be undertaken to inform treatment planning for patients with C3G (Table 3)³. However, the 2021 KDIGO guidelines only recommend evaluations for complement dysregulation in cases of IC-MPGN where no underlying aetiology has been found after extensive workup².

Table 3. Evaluations for complement dysregulation^2,3. AP50, complement alternate pathway activation 50%; Bb, cleavage product of factor B; C3Nefs, complement component 3 nephritic factors; C4Nefs, complement component 4 nephritic factors; C5Nefs, complement component 5 nephritic factors; CFHR5, complement factor H-related 5; CH50, complement haemolytic activity 50%; DGKE, diacylglycerol kinase epsilon; FB, factor B; FBAA, factor B autoantibodies; FH, factor H; FHAA, factor H autoantibodies; FI, factor I; Ig, immunoglobulin; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; MLPA, multiplex-ligation-dependent probe amplification; sMAC, soluble membrane attack complex. *Recommended in Heiderscheit et al 2022³, but not included in recommended evaluations for complement dysregulation in 2021 KDIGO Guidelines².

Some complement assays may require referral to specialist/research laboratories, and interpretation of complement assays may require expert consultation².

Determining the degree and cause of dysregulation in the complement pathways may facilitate development of tailored treatment plans³

Although no complement inhibitors have been approved for use in patients with C3G^21,22, numerous investigational candidates that target the complement system are in clinical development for C3G and other types of complement-mediated kidney diseases (CMKDs)²³.

Challenges with C3 glomerulopathy diagnosis in practice

Aspects that can confound or complicate C3G diagnosis include^3,24,25:

• Borderline immunofluorescence results^2,16 (e.g. for C3G versus IC-MPGN)
• Biopsies changing from IC-MPGN to C3G over time³ (or vice versa¹⁶)

The boundary between C3G and IC-MPGN can be unclear, and dysregulation of the alternative complement pathway has been identified in some patients with IC-MPGN²⁰.

In some cases, C3G may be triggered by infectious diseases, which can present a challenge for differentiating C3G diagnosis from PIGN¹.

Additionally, not all antibodies used for routine immunofluorescence studies detect deposition of the predominant C3 cleavage product (C3dg), so complement fragment deposition may be missed²⁴.

Treating C3 glomerulopathy

Current treatment strategies for C3 glomerulopathy (C3G) are largely limited to symptomatic treatments^2,3. These include:

• angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) to reduce proteinuria and improve blood pressure control²
• immunosuppressants such as mycophenolate mofetil (MMF) and glucocorticoids for moderate-to-severe disease², to suppress kidney inflammation³

C3G treatments are summarised in Figure 3.

Figure 3. Recommended treatments for C3 glomerulopathy². ACEi, angiotensin-converting enzyme inhibitor; ARBs, angiotensin receptor blockers; C3G, C3 glomerulopathy; CV, cardiovascular; MMF, mycophenolate mofetil. *Defined as moderate-to-marked proliferation on biopsy and proteinuria (>2 g/d)². †For hypertension/proteinuria, other strategies include mineralocorticoid receptor antagonists, loop and thiazide diuretics².‡Notes: Although eculizumab may be considered in this population, there is no clear evidence of benefit from eculizumab treatment in patients with C3G², eculizumab is not FDA- or EMA-approved for use in patients with C3G (so use for this indication is considered off-label)^21,34. §For hyperlipidaemia, other options include bile acid sequestrants, fibrates, nicotinic acid, ezetimibe, PCSK9 inhibitor, lipid apheresis².

Guidelines note eculizumab may be considered for patients with moderate-to-severe C3G, if no response is achieved with MMF plus glucocorticoids². However, eculizumab is not currently approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for use in patients with C3G^35,36, and such use is considered off-label³. A few studies have indicated limited benefit from eculizumab in C3G, with more than 50% of patients non-responsive after >1 year of eculizumab treatment^37,38.

No disease-specific treatments have been approved for C3G^1,21,22; however, various investigational drugs that target the complement system are in clinical development for this indication³⁹.

Addressing unmet needs in C3G treatment

Below, Dr Edwin Wong describes some of the most significant obstacles and unmet needs for management of C3 glomerulopathy (C3G).

Unmet needs in C3G management

In C3G, there are pressing needs for:

• improved and earlier diagnosis of C3G^1,40,41
• effective treatment strategies that target underlying disease drivers^1,3,42,43

Despite the use of supportive and immunosuppressive treatments³⁰, the poor outcomes observed in patients with C3G today are similar to outcome data described more than 50 years ago⁴¹. Patients with C3G are at high risk of kidney failure^30,44. Even after kidney transplant, there is a high risk of disease recurrence⁴⁴. This persistently poor prognosis is considered to reflect the lack of effective, targeted treatment options for C3G^1,3,43.

In a recent multicentre retrospective cohort study of patients with C3G, 43% of patients with C3G reached kidney failure after only 5 years, despite 84% receiving immunosuppression³⁰

There is also a need for a better understanding of the natural history of C3G¹, and many knowledge gaps persist^3,4. An improved understanding of the natural history of C3G may:

• enable integration of clinical data with findings from pathology, genetic and complement biomarker studies⁴
• help to inform duration of treatment¹
• clarify generalisability and relevance of natural history data to ethnically diverse populations²⁹
• help to clarify if changes in dysregulated pathways may occur or normalise over time¹

Investigational treatments in clinical development for C3G

To address the lack of targeted treatments for C3G^1,43 a range of investigational treatments are in clinical development^23,39. Key therapeutic targets within the complement cascade that are being investigated in clinical trials for C3G are summarised below²³ (Table 5).

Table 5. Complement inhibitors in clinical trials for C3G²³*. aHUS, atypical hemolytic uremic syndrome; C3G, complement component 3 glomerulopathy; C3GN, C3 glomerulonephritis; DDD, dense deposit disease; FB, factor B; FH, factor H; IC-MPGN, immune complex membranoproliferative glomerulonephritis; IgAN, immunoglobulin A nephropathy; LN, lupus nephritis; MASP-2, mannose-binding lectin-associated serine protease-2; MN, membranous nephropathy; PNH, paroxysmal nocturnal haemoglobinuria. *Danicopan (a Factor D inhibitor) was previously investigated for C3G, IC-MPGN and DDD in clinical trials that have since been completed (NCT03124368, NCT03369236) or terminated (NCT03459443), and no longer appears to be under active development for CMKDs²³. †Study has passed its completion date and status has not been verified in more than two years²³. Note: This is intended as a summary and is not an exhaustive list of all complement inhibitors in clinical development. Information current as of 9 June 2023.

As C3 convertase overactivation appears central to the pathophysiology of C3G, investigational treatments that target the C3/C3 convertase axis by inhibiting C3, Factor B or Factor D are emerging as promising therapeutic approaches for C3G¹.

See our summary figure on investigational targets in the complement system for complement-mediated kidney diseases (CMKDs)

Find out more about types of CMKDs, and learn about their burden and impact

Learn about the complement system and how it becomes dysregulated in disease

Learn about the burden and pathophysiology of IgA nephropathy, another type of CMKD