A Narrative Review of C3 Glomerulopathy: From Pathogenesis to Targeted Therapy

Abstract

Purpose of the review:

Complement factor 3 (C3) glomerulopathy (C3G) is an ultra-rare, progressive, complement-mediated kidney disease. Despite many advances in the understanding of its underlying pathophysiology, C3G remains a clinical challenge due to the overall burden of disease, diagnostic complexity, poor prognosis, lack of approved therapies, and limited access to drugs for kidney diseases in Canada. This narrative review explores the diagnosis and management of individuals with C3G, including novel complement-mediated therapies and their potential impact on patients and outcomes.

Sources of information:

This narrative review is based on the best available data, current treatment guidelines, and the authors’ clinical experiences. Information for the patient perspective section was collected through discussions with two individuals with C3G.

Methods:

A panel of Canadian nephrologists who actively care for individuals with C3G was assembled. A rare disease advocate and two individuals with C3G were invited to share their lived experiences. The authors conducted a comprehensive review of the literature to explore the state of the science and future directions in C3G, highlighting current limitations and unmet needs.

Key findings:

C3 glomerulopathy is caused by dysregulation of the alternative complement pathway, leading to the deposition of complement proteins and their cleavage products in kidney glomeruli. The consequence of deposition of C3 is glomerular inflammation and tissue damage, which lead to proliferative glomerulonephritis and remodeling of the glomerular capillary walls. Individuals diagnosed with C3G experience significant symptoms that adversely impact their quality of life. Nearly half of patients develop kidney failure within 10 years of diagnosis. C3 glomerulopathy recurrence after kidney transplant occurs in more than half of patients. Severity of proteinuria and reduced estimated glomerular filtration rate (eGFR) are among the most important clinical predictors of kidney failure with further research required for the utility of biomarkers to guide prognosis. There is no established standard of care and no therapies specifically approved for individuals with C3G in Canada. Complement-directed therapies, iptacopan and pegcetacoplan, have demonstrated significant reductions in proteinuria and stabilization in kidney function, offering hope for individuals with C3G, including post-transplant. This review offers an up-to-date synthesis of current knowledge on C3G for Canadian nephrologists at a juncture where targeted therapies are becoming available.

Limitations:

A systematic review of the literature was not undertaken. Key takeaways are based on currently available evidence, of which head-to-head clinical trials are lacking. The possibility for bias based on the authors’ clinical experiences may have occurred.

Introduction

Complement factor 3 (c3) C3 glomerulopathy (C3G) is an ultra-rare, complement-mediated kidney disease.^1,2 It is caused by dysregulated activation of the alternative pathway (AP), leading to deposition of complement proteins and their cleavage products in glomeruli. The consequence of C3 deposition is glomerular inflammation and tissue damage, which lead to proliferative glomerulonephritis and remodeling of glomerular capillary walls. ³

Historically, membranoproliferative glomerulonephritis (MPGN) was classified into 3 types based on the pattern of immune deposits on electron microscopy (EM).^4,5 Since 2010, it has been determined that immunofluorescence (IF) may better reflect the underlying pathogenesis of MPGN. ⁶ It was established that MPGN type 2/dense deposit disease (DDD) and C3-dominant MPGN result from complement AP abnormalities causing glomerular C3 deposition, characterized by C3-dominant IF. Another form of MPGN, immune complex (IC)-MPGN, arises from immunoglobulin (Ig) and/or IC deposition, thought to result from activation of the classical complement pathway. ⁷ Importantly, other causes of IC deposition (eg, lupus, cryoglobulins, monoclonal proteins) must be excluded in this circumstance. Although considered distinct, IC-MPGN in which no underlying driver of IC formation has been identified, and C3G show similar rates of low serum C3, C3 nephritic factor (NeF) autoantibody, and complement mutations, suggesting IC-MPGN and C3G may exist on a spectrum of C3G with dysregulation of complement AP as the driver of disease. However, while C3G shows isolated, dominant C3 deposition with minimal Ig, IC-MPGN shows C3 deposition alongside prominent Ig and classical pathway complement components. Some cases of IC-MPGN may be infection-related and, if persistent or if underlying complement defects are present, may fail to resolve and could be re-classified as C3G if re-biopsied. ⁸

Among individuals with C3G, those with electron-dense “sausage-like” deposits along the glomerular basement membrane are diagnosed with DDD, while those with C3-dominant glomerulonephritis without DDD deposits are classified as C3 Glomerulonephritis (C3GN).^7,9,10 There remains disagreement as to whether these are separate conditions or also exist on a spectrum but will be considered as part of the same condition here.

C3 glomerulopathy is a progressive glomerulonephritis, with up to 50% of affected adults developing kidney failure within 10 years of diagnosis.^11-13 Individuals with C3G face a substantial disease burden that significantly impacts their quality of life and emotional health. ¹⁴

As of March 2026, no disease-specific therapies have been approved for C3G in Canada, and an optimal management approach beyond supportive care has yet to be established. ¹⁵ However, the clinical landscape is rapidly evolving. Complement-directed therapies, iptacopan and pegcetacoplan, are now in late-stage development.^16,17 There is growing interest in the potential of these novel complement-targeted therapies to improve outcomes in C3G.

This review offers an updated synthesis of current knowledge on C3G and seeks to highlight ongoing clinical and access-related gaps that hinder optimal care.

Methods and Sources of Information

A panel of Canadian nephrologists with expertise in C3G was convened. To incorporate patient-centered perspectives, the panel included a national rare disease advocate and two individuals (names anonymized for privacy) living with C3G. These contributors offered insights into the lived experience of individuals with a rare kidney disease, helping to ground the clinical and scientific discussion in a real-world context.

The authors undertook a review of the C3G literature. Literature searches were conducted in PubMed and Google Scholar using terms such as “C3 glomerulopathy,” “complement system,” and “complement-directed therapy.” Additional searches using terms including “iptacopan,” “pegcetacoplan,” and “complement-directed therapy” were performed on ClinicalTrials.gov to identify randomized controlled trials (RCTs). Only English-language, peer-reviewed publications were included. The data were synthesized and critically appraised by the authors to highlight emerging evidence, existing limitations, and areas of unmet need.

Review

What Is Already Known

Pathophysiology

Complement Activation via the Alternative Pathway

There are three interrelated pathways through which complement can be activated: classical, lectin, and alternative. The AP is constitutively active at low levels and tightly regulated to maintain a balance between physiological activation and harmful overactivation. ¹⁸

Alternative pathway activation is initiated by spontaneous hydrolysis of a thioester bond within C3, resulting in the formation of C3(H2O), a process known as “tick-over.” ¹⁹ C3(H2O), like C3b, binds to complement factor B (CFB) and is cleaved by complement factor D to form C3 convertase (C3bBb). C3 convertase, which is stabilized by properdin (CFP), cleaves C3 to C3a and C3b. C3a is an anaphylatoxin that promotes inflammation, while C3b drives an auto-amplification loop that generates C3 convertase and C3b. ²⁰ Once a critical density of C3b is reached, C5 convertase is formed. C5 convertase cleaves C5 to form C5b, triggering the terminal complement cascade, leading to the assembly of the C5b-9/membrane attack complex (MAC) and cell lysis (Figure 1A). ¹⁸

Figure 1.

The complement AP is overactive in C3G. (A) The 3 activation pathways of complement merge in the activation of C3 to C3b via C3 convertase. C3b promotes the formation of C5 convertase to activate C5 to form the C5a and C5b, which initiate the terminal pathway, resulting in the assembly of the MAC on cells and, in turn, resulting in cell injury, inflammation, and thrombosis. (B). Complement factors B and D (CFB, CFD) and CFP participate in the formation of C3 convertase, generating C3b. C3b can engage into an amplification loop of C3 activation. This step is regulated in the fluid phase by CFH and on cell surfaces by CR1 and decay accelerating factor (DAF). The fate of C3b on cell surfaces is determined by fluid-phase and surface-bound regulators. Fluid-phase (CFH, CFI) and membrane-anchored cofactor proteins (MCP, CR1) generate the inactive iC3b and further C3b split products (C3d, C3e, C3f, C3g), preventing terminal complement activation. Solid lines represent the physiological pathways; dotted lines represent the pathways suppressed by regulators. In C3G, mutations and autoantibodies (purple font) predominantly affect fluid-phase regulators, resulting in excess formation of C3b inactivation products (purple arrows and box), which can be deposited in the glomerulus.

The AP is regulated by fluid-phase or membrane-bound proteins, including complement factor H (CFH), complement factor I (CFI), membrane-anchored cofactor (MCP), decay-accelerating factor (DAF), and complement receptor 1 (CR1), which promote inactivation of C3b and other C3b fragments (Figure 1B). ³

Pathophysiology of C3 Glomerulopathy

Dysregulated AP activation can result from loss of function of regulatory proteins or gain of function of effector proteins. These abnormalities can be caused by acquired autoantibodies and/or genetic abnormalities:^3,15,18

• Autoantibodies to convertases, eg, C3-, C4-, and C5-nephritic factors (eg, C3NeFs).

• Autoantibodies to complement regulatory proteins, eg, Factor H (FH) autoantibodies (FHAA).

• Loss-of-function mutations in CFH and CFI.

• Gain-of-function mutations in C3 and CFB.

In each scenario, C3 convertase activity is enhanced, amplifying the complement cascade. This leads to excessive consumption of C3 and deposition of C3 in the kidneys, which drives glomerular inflammation and damage. ³

Genetic variants and/or genomic rearrangements are identified in approximately 25% of individuals with C3G.^11-13 The most prevalent genetic variants result in dysregulation of C3 convertase, although the presence of such mutations alone does not usually significantly increase the risk of C3G onset. ²¹ C3 glomerulopathy differs from complement-mediated thrombotic microangiopathy (TMA) in the site and nature of complement dysregulation. C3 glomerulopathy is characterized by dysregulation of the alternative complement pathway predominantly in the fluid-phase and glomerular microenvironment, leading to glomerular C3 deposition and proliferative glomerulonephritis. In contrast, complement-mediated TMA atypical hemolytic uremic syndrome (aHUS) involves dysregulation of the AP at the endothelial surface, leading to systemic microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Genetic mutations in complement regulatory genes (CFH, CFI, CD46, etc) are more commonly identified in aHUS, and these mutations directly impair complement regulation on endothelial cells, precipitating widespread microvascular thrombosis.^11,20,22-24

C3NeFs are the most common acquired complement defect in C3G. They bind to and stabilize C3 convertase, preventing its inactivity and causing persistent activation of AP. C3NeFs against C3bBb are detected in 86% of individuals with DDD and 46% of individuals with C3GN in contemporary reports.^13,25 Half of patients with disease-associated mutations also have C3NeFs. ¹³ Other autoantibodies, including C4NeFs, C5NeFs, FHAAs, and Factor B autoantibodies (FBAAs), occur at a lower frequency. ²⁶ The prognostic role of C3NeFs in C3G pathophysiology is unclear, as levels of C3NeFs can fluctuate during the clinical course without any association with disease activity and treatment effect.^25,27

When C3-dominant glomerulonephritis is diagnosed in adults >50 years of age, it is often associated with an underlying monoclonal gammopathy, in which the paraprotein targets regulatory elements of the AP, leading to complement activation.^28,29 Conversely, IC-MPGN can represent a primary, complement-mediated process, and secondary causes should be systematically excluded in both IC-MPGN and suspected C3G, particularly in older patients. ³⁰

Epidemiology and Clinical Features

The global incidence of C3G is estimated at one to two cases per one million,^1,31 and point prevalence estimates range from five to 140 cases per one million. ¹¹ Because C3G is a relatively newly defined disease entity, the ability to identify the condition in standard real-world data sources such as electronic health records or claims data is limited.

C3 glomerulopathy predominantly affects individuals <40 years, and 30% to 40% of individuals are diagnosed under 18 years of age.^{1,12,13,32,33} The Registry of Rare Kidney Diseases (RaDaR) and the European Rare Kidney Disease Registry (ERKReg) report that 60% to 80% of individuals experience childhood onset.^34,35 Individuals who develop C3G in adulthood tend to exhibit more severe symptoms and a more rapid disease progression compared to pediatric patients. ³⁴ Clinically, it is important to understand that C3G reflects chronic AP dysregulation that damages kidneys at a rate determined by the individual’s degree of dysregulation. The disease can be subclinical or difficult to detect. In these cases, the dysregulated AP can be triggered (by infections, medications, or surgery), which may result in periods of accelerated damage and inflammation.

Diagnosis

Diagnostic Workflow

The clinical presentation of C3G can be variable, reflecting the spectrum of underlying acquired and genetic factors. ¹⁰ Approximately 10% of individuals present with proteinuria <1 g/day, and 30% have a normal estimated glomerular filtration rate (eGFR). ³⁶ More commonly, individuals present with non-specific features of glomerulonephritis: hematuria, subnephrotic (<3.5 g/d) or nephrotic (≥3.5 g/d) proteinuria, hypertension, and peripheral edema.^37,38 Individuals with DDD may present with retinal drusen and acquired partial lipodystrophy. ³⁹

Laboratory screenings, including a metabolic panel, complete blood count, complement (C3 and C4) levels, autoimmune panel, infectious disease panel, serum protein electrophoresis and immunofixation, serum free light chains, and urine protein-creatinine ratio (UPCR), typically comprise the first step in diagnosis. ²⁶ Approximately 45% to 70% of patients have low C3 levels,^{1,12,13,26,28,33,36} but a normal C3 level does not rule out C3G, and complement levels have not been shown to correlate with disease severity. ²⁶

Kidney biopsy is the gold standard for diagnosis. Light microscopy may reveal mesangial hypercellularity, endocapillary hypercellularity, and crescents, while some patients have a membranoproliferative pattern of injury. ⁹ Rarely, light microscopy may be normal. ⁹ Given the non-specific appearance of C3G under light microscopy, C3-dominant IF staining, defined as being at least two orders of intensity greater than other immune reactants, is required for a definitive diagnosis.^10,40 Electron microscopy is then used to differentiate DDD and C3GN, based on the appearance of the dense deposits of C3. ⁹

Differential Diagnosis

An initial workup should evaluate for monoclonal gammopathy and aim to rule out infection-related glomerulonephritis (IRGN).^11,26 A biopsy of glomerulonephritis associated with monoclonal gammopathy may seem C3 dominant; however, monoclonal Ig deposits may be masked on routine IF.^11,40,41 Infection-related glomerulonephritis, which may be driven by acquired CFB autoantibodies, ⁴² can present with low serum C3 and C3-dominant deposition, but assessment at least three months after the initial biopsy should find resolution of kidney function without intervention. ⁴³ If kidney function continues to decline after this period, a repeat biopsy is warranted, and the disease should be reclassified as C3GN if C3-dominant deposition is found.^11,43

Supplemental Tests

Functional assays of the AP (C3, C4, CH50, AP50, and serum CFH), genetic testing (for mutations in C3, CFH, CFI, CFB, CFHR1-5),^11-13 and autoantibody screening (for C3-, C4-, and C5NeFs) can determine the driver of AP dysregulation, which may be useful in guiding treatment.^26,30 However, not all cases of C3G have an identifiable cause of the AP dysregulation. In addition, nephritic factor testing in Canada lacks standardization and is available only at select centers, with potential funding limitations.

New findings from biomarker and genetic studies are shaping treatment decisions. Although serum C3 is not associated with prognosis, a French cohort demonstrated that normal C3/high soluble C5b-9 (sC5b-9) or low C3/normal sC5b-9 were independently associated with an increased risk of progression to kidney failure. ³² A cluster analysis conducted by the Italian group indicates that patients exhibiting solid-phase complement activation, characterized by low nephritic factor levels and systemic complement activation, experience reduced renal survival when treated with current therapies. ⁴⁴ However, biomarker interpretation is challenged by biological and analytic variability: complement activation can fluctuate over time and with intercurrent triggers, single time-point measurements may not reflect the dominant pathogenic mechanism in an individual, and assays (particularly nephritic factor testing) lack standardization and are variably available, which can limit comparability across centers and constrain routine clinical use. Thus far, the presence of nephritic factors has not been associated with prognosis, but their presence may influence response to immunosuppression. ⁴⁵ Kidney Disease Improving Global Outcomes (KDIGO) guidelines also recommend complement testing as part of the diagnostic workup, as findings can inform management and distinguish patients who may benefit from immunosuppression or complement inhibition. ¹⁵ However, complement tests alone should not dictate therapy; clinical features remain central to management decisions, and recommendations may evolve with the introduction of complement-directed therapies.

Management of C3 Glomerulopathy

There are no approved treatments and no established standard of care for C3G not associated with monoclonal gammopathy due to a lack of randomized control trial (RCT) data. While organizations such as KDIGO have put forth a therapeutic approach, this is based on expert opinion. ¹⁵ The management of C3G in Canada is based on international consensus and national expertise and involves supportive care and non-specific immunosuppression. ⁴⁶

Supportive Care

Current first-line therapy recommendations include angiotensin-converting enzyme inhibitors (ACEis) or angiotensin-receptor blockers (ARBs), and lifestyle modifications, to manage blood pressure and reduce proteinuria.^11,15,26 No good evidence currently supports the use of sodium glucose transport 2 inhibitors (SGLT2is) in C3G. However, given the demonstrated reduction in progression of non-diabetic chronic kidney disease (CKD), ⁴⁷ it should be considered for those with residual proteinuria and no safety concerns with concomitant disease-targeting treatments.

While renin-angiotensin-aldosterone inhibitors (RAASis) and SGLT2i may reduce proteinuria, they do not address the underlying inflammatory component of C3G. Therefore, these medications can reduce GFR decline, but patients may continue to progress due to the untreated underlying AP dysfunction and resultant inflammatory process.^48,49

Immunosuppressive Therapy with Mycophenolate Mofetil and Corticosteroids

The recommended first-line treatment for moderate-to-severe disease, ¹⁵ defined as proteinuria >1g/day and hematuria or declining kidney function for ≥6 months despite supportive care, is broad immunosuppression via mycophenolate mofetil (MMF) and oral glucocorticoids (GCs).^15,50 Individuals with proteinuria < 1g/day may still be at risk for progressive kidney disease, so this threshold should not be considered the sole benchmark for initiating therapy. For individuals with rapidly progressive crescentic glomerulonephritis, aggressive immunosuppression with intravenous methylprednisolone pulse therapy, followed by MMF plus oral GC, is warranted. ⁵⁰ Some experts will also consider cyclophosphamide instead of MMF.

Mycophenolate mofetil plus GCs have been shown to reduce proteinuria and stabilize eGFR.^51-53 However, evidence to date has been derived from retrospective cohort studies and effectiveness has not been consistently demonstrated across cohorts (Table 1).^{12,13,28,54,55} Patients treated with non-directed immunosuppression still progressed to end-stage kidney disease (ESKD) at 10 years, at a rate similar to untreated patients.^1,13 Standard immunosuppressive therapies given to transplant recipients to prevent acute and/or chronic allograft rejections include high-dose mycophenolate acids and corticosteroids, but these are unable to delay recurrence or inhibit accelerated C3G-related graft loss. ⁵⁶ Importantly, the above therapies do not suppress the underlying cause of C3G, namely, dysregulation of the AP, ⁵⁷ and the adverse effects of long-term, broad immunosuppression have a substantial negative impact on quality of life.^14,58,59

Table 1.

Clinical Data on Immunosuppressive Therapy With MMF and Corticosteroids.

Study	Study type	Treatment groups	Proteinuria remission	Kidney function	Follow-up comparison between treatments
Häffner et al 60	Case series	MMF + CS + Plasma (n = 4)	n = 3	↑ (n = 3); unchanged (n = 1)	NA
Caliskan et al 55	Retrospective cohort	MMF (n = 27) CS or CP (n = 23) No IS (n = 16)	NA	GFR ↓ ≥50%: n = 8/27 GFR ↓ ≥50%: n = 4/23 GFR ↓ ≥50%: n = 5/16	No difference
Bharati et al 61	Retrospective analysis, single center	MMF ± CS (n = 17)	n = 11	↑ (n = 4), = (n = 7), ↓ (n = 6)	NA
Avasare et al 51	Case series	MMF + CS (n = 30) CS ± CNI ± Rituximab ± CP (n = 43)	n = 20 n = 15/43	Unchanged NA	No statistical comparison
Yeter et al 62	Retrospective observational, single center	MMF + CS (n = 7) CS + CP (n = 14)	n = 3/7 n = 8/14	Unchanged (n =5); ↓ (n = 2) Unchanged (n =6); ↓ (n = 8)	No difference
Rabasco et al 53	GLOSEN retrospective, multicenter cohort	MMF + IS (n = 22) Other IS (n = 18) No IS (n = 20)	n = 19/22 n = 9/18 n = 5/20	=/↑ (n = 22) =/↑ (n = 8) =/↑ (n = 6)	Remission: MMF + IS superior
Caravaca-Fontan et al 52	GLOSEN retrospective, multicenter, observational cohort	MMF + CS (n = 42) Other IS (n = 29) Eculizumab (n = 9) No IS (n = 17)	n = 33/42 n = 7/29 n = 3/9 n = 3/17	=/↑ (n = 33) =/↑ (n = 7) =/↑ (n = 3) =/↑ (n = 3)	Kidney survival: MMF + CS superior
Ravindran et al 28	Retrospective observational, single center	MMF ± CS (n = 24) CS (n = 12) No IS (n = 34)	n = 3/24 n = 5/12 n = 13/34	Kidney failure: n = 9 Kidney failure: n = 0 Kidney failure: n = 3	No difference
Pinarbaşi et al 63	Retrospective, multicenter	MMF/AZA (n = 31) CS (n = 11) Other IS (n = 16)	n = 13/31 n = 9/11 n = 7/16	NA	No difference
Ali and Sathe 64	Retrospective, observational cohort	MMF + CS (n = 6)	n = 6/6	Kidney survival: n = 6	NA

Note. AZA= azathioprine; CS = corticosteroids; CP = cyclophosphamide; CNI = calcineurin inhibitors; IS = immunosuppressants; MMF = mycophenolate mofetil; NA = not available; =, unchanged; ↑ = improved; ↓ = worsened.

Terminal Complement Blockade (Eculizumab) and Avacopan

Eculizumab, an anti-C5 monoclonal antibody that blocks the terminal complement pathway, has been used as rescue therapy for individuals who do not respond to MMF and GC therapy.^15,50 However, individuals with C3G treated with eculizumab continue to have low C3 and elevated C3d, ⁶⁵ suggesting that eculizumab does not address the underlying pathophysiology of C3G. This is supported by clinical data demonstrating the limited effectiveness of eculizumab in reducing proteinuria and improving disease outcomes.^66-70 Across multiple cohorts, only about 23% of patients achieve a global clinical response, with an additional 23% showing partial response and 54% experiencing no meaningful improvement in renal function or proteinuria.^15,67 The mechanistic basis for this limited efficacy is a result of inhibition of C5 activation and failure to address the persistent upstream C3 convertase activity that drives glomerular injury in C3G. ⁶⁵ In contrast, aHUS is characterized by terminal pathway activation at the endothelial surface, where C5 blockade is sufficient to halt microangiopathic injury and is associated with high response rates.^15,65 Blockade of terminal complement activation may also increase susceptibility to infections, necessitating vaccination against meningococcal infections before initiating treatment and often antibioprophylaxis. ⁷¹ The time commitment of eculizumab infusions has been reported to negatively impact quality of life. ¹⁴

Avacopan, an oral small molecule that blocks the C5a receptor, has been studied in a phase 2 Controlled Trial Evaluating Avacopan in C3 Glomerulopathy (ACCOLADE) in C3G. It did not meet the primary outcome of histological improvement at six months, but there was a statistically significant improvement in proteinuria at 16 weeks, which was lost at 26 weeks. ⁷²

Literature Updates

Clinical Predictors of Disease Course

Due to its progressive nature, C3G carries one of the highest risks for kidney failure of all primary glomerular diseases.^73,74 Cohort studies reported in 2025 have expanded the understanding of risk factors and surrogate biomarkers in C3G.^35,75,76 In addition to age, the degree of proteinuria and declining eGFR are key clinical predictors of kidney failure. ³¹ Histologic features (eg, the chronicity score) and hypertension have also been linked to outcomes in C3G,^{12,21,33,74,77,78} indicating the importance of early and timely diagnosis to reduce kidney damage.

Proteinuria and Estimated Glomerular Filtration Rate

There is strong epidemiological evidence for the association of proteinuria and eGFR with the progressive loss of kidney function in glomerulonephritis. ⁷⁹ In addition to proteinuria serving as a surrogate biomarker for glomerular inflammation, it may also contribute to the progression of kidney disease by facilitating tubular inflammation, leading to scarring and impaired kidney function. ⁸⁰ While eGFR <60 mL/min/1.73 m² and nephrotic-range proteinuria at baseline were associated with the worst outcomes, time-averaged proteinuria was also predictive of ESKD.^{12,31-33,35,52,54,55,76,81}

Histopathological Features

Based on findings in lupus nephritis, ⁸² a C3G Histologic Index (C3G-HI) has been proposed for the assessment of activity (ongoing inflammation) and chronicity (irreversible structural damage) in biopsy samples (Table 2). ¹²

Table 2.

C3 Glomerulopathy Histopathology Index.

Component	Definition	Score
Activity score, 0-21
Mesangial hypercellularity	Percentage of glomeruli with >3 mesangial cells per mesangial area	0 = none, 1 = 1-25%, 2 = 26-50%, 3 = >50%
Endocapillary proliferation	Percentage of glomeruli with an increased number of cells within glomerular capillary lumina, causing luminal narrowing	0 = none, 1 = 1-25%, 2 = 26-50%, 3 = >50%
Membranoproliferative morphology	Percentage of glomeruli with GBM duplication with or without endocapillary proliferation	0 = none, 1 = 1-25%, 2 = 26-50%, 3 = >50%
Leukocyte infiltration	Percentage of glomeruli with glomerular capillary infiltration by ≥3 neutrophils and/or macrophages	0 = none, 1 = 1-25%, 2 = 26-50%, 3 = >50%
Crescent formation	Percentage of glomeruli with cellular and/or fibrocellular crescents	0 = none, 1 = 1-10%, 2 = 11-25%, 3 = >25%
Fibrinoid necrosis	Percentage of glomeruli with the presence of ≥2 of fibrin, karyorrhexis, and GBM rupture	0 = none, 1 = 1-10%, 2 = 11-25%, 3 = >25%
Interstitial inflammation	Percentage of cortical tubulointerstitial are with inflammation in non-fibrotic cortex	0 = <10%, 1 = 10-25%, 2 = 26-50%, 3 = >50%
Chronicity score, 0-10
Glomerulosclerosis	Percentage of glomeruli with global and segmental sclerosis	0 = <10%, 1 = 10-25%, 2 = 26-50%, 3 = >50%
Tubular atrophy	Percentage of cortical tubulointerstitial area involved with interstitial fibrosis	0 = <10%, 1 = 10-25%, 2 = 26-50%, 3 = >50%
Interstitial fibrosis	Percentage of cortical tubulointerstitial area with interstitial fibrosis	0 = <10%, 1 = 10-25%, 2 = 26-50%, 3 = >50%
Arterio- and arteriolosclerosis	Intimal thickening ≥ thickness of media	0 = absent 1 = present

Source. Adapted from Bomback et al. ¹²

Note. GBM = glomerular basement membrane.

The C3G-HI chronicity score and its individual components were consistently associated with worse disease outcomes^{12,33,54,75,76,78,83} These findings are perhaps unsurprising, because a high chronicity score indicates severe glomerular damage and suggests longer disease duration. While activity score was associated with disease outcomes, it was correlated with baseline proteinuria and not found to be an independent predictor of kidney outcome.^12,54,76,78 Because activity score represents acute reversible changes, changes in its components may be more useful for assessing treatment response (discussed under the section Histology and C3 Deposition).^84,85 The C3G-HI has been validated in external populations in Spain, the United States, and in C3G associated with monoclonal gammopathy cohorts.^12,78,86 It is most applicable when the biopsy meets accepted criteria for C3G. Its use is limited in “C3G-like” cases driven by monoclonal gammopathy or masked Ig deposits, where the overall index may be less biologically aligned and should be interpreted cautiously.

More intense C3 staining is associated with worse kidney survival and greater eGFR decline in IgA nephropathy; ⁸⁷ however, there is no evidence linking C3 staining intensity to outcomes in C3G. ⁸³ A recent study found that elevated glomerular C5b-9 was associated with poorer kidney prognosis in individuals with DDD. Although this suggests that the terminal pathway may play an important role in kidney injury, C5b-9 may serve as a marker of disease progression rather than activity. ⁸⁸

Emerging Complement-Directed Therapies

Current treatment options in C3G fail to address the key pathogenic mechanism—uncontrolled fluid-phase AP C3 convertase activity—that drives persistent glomerular C3 fragment activation, glomerular deposition of C3b split products, and progressive injury. ¹⁵

For the first time, there are therapeutic options to target the proximal AP directly. Pegcetacoplan blocks C3 and C3 convertase formation and iptacopan blocks factor B, inhibiting cleavage of Factor B into Ba and Bb and preventing formation of C3 convertase. By intervening at this step, these agents offer the potential to alter disease course, as supported by emerging clinical trial and real-world evidence.

C3 Inhibition: Pegcetacoplan

Subcutaneous infusion with the C3/C3b inhibitor pegcetacoplan has demonstrated efficacy in both native-kidney and post-transplant recurrent C3G. In an open-label phase 2 study including only patients with native kidneys (n = 8), 48 weeks of pegcetacoplan led to a mean 24-hour UPCR reduction of 51%. ⁸⁹ At week 48, 75% of patients had stable or improved eGFR. An increase in serum C3 and a decrease in serum sC5b-9 were observed, suggesting reduced activation of C3 and the downstream terminal complement pathway. ⁸⁹

The phase 3 Study Assessing the Efficacy and Safety of Pegcetacoplan in Patients with C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis (VALIANT) trial included patients with C3G (n = 96) or primary IC-MPGN (n = 28) in native (n = 115) and post-transplant (n = 9) kidneys who were randomized to pegcetacoplan 1080 mg self-administered twice weekly (n = 63) or placebo (n = 61), both on optimized supportive care. ⁹⁰ In patients with C3G or primary IC-MPGN, at the 26-week primary endpoint, pegcetacoplan reduced geometric-mean UPCR by 68% (P < .0001 vs placebo). The mean eGFR change from baseline at week 26 was −1.5 mL/min per 1.73 m² with pegcetacoplan, contrasting with a −7.8 mL/min per 1.73 m² decline in the placebo group. The composite endpoint of ≥50% UPCR reduction with ≤15% reduction in eGFR was met by 49.2% of pegcetacoplan recipients compared with 3.3% of placebo. ⁹⁰

Efficacy was consistent across subgroups, including those with nephrotic-range proteinuria (UPCR ≥3 g/g), who achieved a 72% reduction in proteinuria, and regardless of baseline immunosuppression status (proteinuria reduced by 70% in those with immunosuppression at baseline, 65% in those without). ⁹⁰ In the post-transplant cohort with recurrent C3G, proteinuria fell by 65% and the between-group eGFR advantage was 9 mL/min/1.73 m² at 26 weeks. ⁹⁰

Renal benefits were sustained through 52 weeks, with patients originally assigned to pegcetacoplan maintaining robust proteinuria reduction (~67%) and minimal eGFR loss (−3.7 mL/min/1.73 m²). Participants initially on placebo saw little change in proteinuria until crossover, after which UPCR improved. Interim biopsy data suggest parallel improvements in glomerular C3 deposition, with 71.4% of pegcetacoplan-treated patients achieving 0 intensity staining after 26 weeks. ⁹⁰

Pegcetacoplan was generally well tolerated. The most frequent adverse events were mild injection site reactions and mild upper respiratory illnesses. ⁹⁰ Inclusion criteria dictated that all participants be vaccinated against Streptococcus pneumoniae, Neisseria meningitidis (types A, C, W, Y, and B), and Haemophilus influenzae (type B). No meningococcal infections were reported during the study period.^89,91 The US Food and Drug Administration approved pegcetacoplan (Empaveli) for C3G in July 2025. ⁹²

Factor B Inhibition: Iptacopan

Iptacopan, an oral, highly selective Factor B inhibitor, has also demonstrated efficacy in both native-kidney and post-transplant recurrent C3G. In an open-label phase 2 study, 12 weeks of iptacopan reduced 24-hour UPCR by 45% from baseline (P = .0003) in patients with native kidneys (n = 16). ⁹³ In the post-transplant group (n = 11), glomerular C3 deposit scores fell from a median of 3.0 at baseline to 0.5 at week 12 (P = .03). ⁹³ Estimated GFR remained stable in both cohorts. This phase 2 study demonstrated for the first time that AP inhibition is associated with changes in complement dysregulation biomarkers, including normalization of serum C3, reduced plasma and urinary sC5b9, and reduced plasma Bb levels, indicating lowered CFB breakdown. ⁹³

The Study of Efficacy and Safety of Iptacopan in Patients with C3 Glomerulopathy (APPEAR-C3G) is the pivotal phase 3 trial evaluating the safety and efficacy of iptacopan in patients with native kidneys. ¹⁷ This double-blind, randomized study included a six-month placebo-controlled phase where patients were assigned to receive iptacopan 200 mg twice daily (n = 38) or placebo (n = 36), followed by a six-month open-label extension. After six months, iptacopan plus supportive care reduced proteinuria by 35.1% vs placebo (P = .0014, 95% confidence interval [CI] = 13.8%, 51.1%). ¹⁷ The iptacopan group was more likely to achieve the composite renal endpoint of ≥50% UPCR reduction with ≤15% eGFR loss compared to the placebo group (30% vs 6%; odds ratio: 7.15, 95% CI = 1.43, 35.72, P = .0166). The change in eGFR at six months was 1.30 mL/min per 1.73 m² in the iptacopan group compared with −0.86 mL/min per 1.73 m² in the placebo group. Post-hoc analysis assessed within-arm changes in eGFR slope from pre-treatment to the six-month double-blind period. The iptacopan arm showed slope stabilization during treatment, with a significant attenuation in the rate of decline (change in slope: −10.75 mL/min/1.73 m²/year to −0.03 mL/min/1.73 m²/year; P = .0057). The placebo arm showed a smaller, non-significant slope change (−7.64 mL/min/1.73 m²/year to −3.08 mL/min/1.73 m²/year; P = .2267). At six months, iptacopan reduced C3 deposits, increased serum C3, and decreased sC5b-9 measures (all P ≤ .0053). ¹⁷

Renal benefits were sustained or improved at 12 months. Reduction in proteinuria was maintained (~40% from baseline), and more patients (45%) achieved the composite renal endpoint. ¹⁷ Across three pooled studies (n = 90), the mean annual eGFR slope was −8.32 mL/min/1.73 m²/year in the pre-iptacopan period and −0.70 mL/min/1.73 m²/year following iptacopan initiation, indicating marked attenuation of the prior decline toward stabilization (slope change: +7.62 mL/min/1.73 m²/year; P < .0001). ⁹¹

Across studies, iptacopan was generally well tolerated with the most common adverse events of mild‑to‑moderate gastrointestinal symptoms.^93-95 Inclusion criteria dictated that all participants be vaccinated against S. pneumoniae and N. meningitidis. One participant who tested blood culture positive for S. pneumoniae during the double-blind period had a pneumococcal infection in the open-label period, which was both resolved with a standard course of antibiotics. ¹⁷ The U.S. Food and Drug Administration approved iptacopan (Fabhalta) for C3G in March 2025. ⁹⁶

Place in Therapy and Integration Into Treatment Paradigm

These are the first phase 3 trials in C3G and IC-MPGN and present an opportunity for the integration of proximal complement blockade into the treatment paradigm for a disease that currently lacks effective therapy.^17,90 Uncertainties remain regarding duration, sequencing, biomarker-guided selection, and the use of MMF and GCs with complement inhibitors. Pegcetacoplan and iptacopan trials both included patients who were not receiving immunosuppressive therapy, and subgroup analysis showed that the effect of pegcetacoplan is present regardless of immunosuppression status. ⁹⁰ In APPEAR-C3G, patients benefited from iptacopan regardless of immunosuppression status; however, the results were not statistically significant. ¹⁷ This suggests that initial treatment with prednisone or MMF may not be needed before complement therapy, although they can be concomitantly prescribed with anti-complement therapies in high-risk disease. Ongoing extension studies should refine positioning, but current evidence supports proximal complement-directed therapy as the emerging standard of care with particular relevance to post-transplant disease, where recurrence is common, may precede clinical manifestations, and is often managed by intensifying maintenance immunosuppression despite high rates of graft loss.

C3 Glomerulopathy Recurrence After Kidney Transplantation

The IC-MPGN and C3G recur post-transplant in 25% to 41% and 60% to 90% of patients, respectively, with similar recurrence rates in C3GN and DDD.^2,56,97 Recurrence rates and timing vary across studies with 1 retrospective analysis of 18 patients reporting recurrence within one month of transplant. ⁵⁶ Newer studies report earlier and more frequent recurrence, likely due to routine surveillance biopsies, more relaxed diagnostic criteria, and greater reliance on EM to detect histologic recurrence at earlier stages. ⁹⁸ Recurrent C3G spans a wide histologic spectrum. When diagnosed early through biopsy, individuals may even show normal glomerular cellularity and have normal renal function and minimal proteinuria, suggesting that histologic recurrence may precede clinical recurrence. As recurrence evolves, mesangial hypercellularity predominates, and approximately 20% to 30% of patients subsequently develop an MPGN pattern. ⁵⁶ Proliferative patterns, crescents, and sclerosis have also been observed. ⁹⁸ C3 staining by IF tends to be more subtle in intensity and may appear focal and segmental rather than diffuse and global as seen in native C3G. In contrast to the tightly packed, sausage-like deposits seen in native DDD on EM, recurrent post-transplant DDD shows waxy, poorly defined deposits that resemble C3GN. These deposits are consistently detected on protocol biopsies at both one and two years after transplantation. ⁹⁸

Data on risk factors for recurrence and graft loss are sparse.^2,57,99 Patient characteristics that influence C3G recurrence and graft loss include younger age at primary diagnosis, ¹⁰⁰ pathogenic gene variants or autoantibodies, and biomarkers for aggressive complement dysregulation (low C3 with high sC5b-9). ⁵⁷

The management of C3G recurrence post-transplant typically involves intensifying maintenance immunosuppression, particularly MMF and corticosteroids, and in selected cases considering early eculizumab. ⁹⁸ However, C3G recurs after transplant because the root cause remains: pathogenic complement gene variants or acquired autoantibodies continue to drive complement dysregulation. Among individuals with recurrence, graft failure rates range from 11% to 77%, with most studies reporting rates >50%.^2,70,101-103 Approximately 50% to 57% of individuals lose their allograft within five years of recurrence.^2,57 Once recurrence occurs in a first transplant, the likelihood of recurrence is increased in subsequent transplants. ³⁵ Faster recurrence (<15 months) is also predictive of worse kidney survival after recurrence. ²

Those who develop recurrence post-transplant are a high-risk and vulnerable population, and effective treatments are urgently needed. Iptacopan and pegcetacoplan target early steps in C3G pathogenesis as compared with therapies that inhibit only the terminal complement pathway, and their use in individuals with C3G recurrence would serve great benefit.

Renal Outcomes and Validity of Surrogate Endpoints in Rare Diseases

In ultra-rare diseases like C3G, trials are generally not adequately powered or with sufficiently long follow-up to reach traditional hard endpoints like kidney failure or death. In this context, validated surrogate outcomes make studies feasible and enable earlier access to therapies. C3 glomerulopathy provides a coherent framework linking disease mechanism to measurable surrogates: dysregulated AP activation leads to glomerular C3 deposition, capillary wall injury, proteinuria, and progressive nephron loss; thus, it is plausible that treatments that interrupt this cascade would decrease glomerular C3 deposition, lower proteinuria, and attenuate eGFR decline. ⁸⁵

Histology and C3 Deposition

Individuals treated with AP-inhibiting agents showed reduced C3 deposit intensity on biopsy, which correlated with biochemical response.^17,90,93 The histologic activity score, which indicates acute glomerular damage, may also be impacted by therapy.^84,90 However, more research is required to validate the role of the activity score as a measure of treatment response, particularly with regard to the timing of improvement. Studies in lupus nephritis demonstrate that activity features may take years to resolve before histological remission is achieved. ¹⁰⁴ It is also unclear how different histological indicators of active disease should be weighted. ⁸⁵ Sampling error, lack of standardized procedures, and feasibility of serial biopsies should also be considered. Nevertheless, in conjunction with proteinuria and eGFR improvement, reduced C3 deposits on biopsy provide confidence that we are addressing the underlying AP dysfunction when treating with iptacopan or pegcetacoplan.^17,90,93

Proteinuria Reduction

The Spanish Group for the Study of Glomerular Diseases (GLOSEN) (n = 85) reported that a ≥50% proteinuria reduction at 6 or 12 months post-diagnosis was associated with improved kidney survival. ¹⁰⁵ The RaDaR registry (n = 44) showed that a decrease in UPCR as little as 20% at 12 months was associated with a lower risk of kidney failure. ³⁵ Both RaDaR and GLOSEN showed that achieving UPCR <1g/day at 12 months was linked to markedly lower kidney failure risk.^35,75 In a larger cohort study of individuals with C3G and IC-MPGN (n = 149), achieving a ≥30% proteinuria reduction at six months was associated with slower eGFR decline, demonstrating the relationship between proteinuria reduction and preservation of kidney function. ⁷⁵

Estimated Glomerular Filtration Rate Stabilization

In the RaDaR and GLOSEN C3G cohorts, the rate of eGFR decline over time was strongly associated with kidney failure risk.^31,35 Data from RaDaR showed that an increase in eGFR slope of +2 mL/min/1.73 m²/year over the first 2 years following diagnosis was associated with improved kidney survival compared to no change in eGFR slope. ³⁵ In the GLOSEN cohort, none of the 36 individuals with a positive eGFR slope experienced kidney failure over 38 months of follow-up. A recent landmark meta-analysis across 66 studies (n = 186 312) in CKD, including those with glomerulonephritis, demonstrated a strong correlation (R ² = 0.97) between treatment effects on total GFR slope and clinical kidney failure outcomes, supporting eGFR slope as a surrogate endpoint. ¹⁰⁶

Global Perspectives on Surrogate Endpoints

Increasingly, regulators worldwide have accepted proteinuria change and eGFR slope as reasonable surrogates for kidney disease progression.^107,108 Observational cohorts have provided quantitative links between early surrogate changes and long-term outcomes and have informed composite responder definitions used in contemporary trials (≥50% UPCR reduction with ≤15% eGFR loss at ~26 weeks). ¹⁰⁹

Consistent treatment effects across patient subsets in various clinical trials, irrespective of genotype, transplant status, or background immunosuppression, further support the external validity of these endpoints.^90,93,95 A 2023 Kidney Health Initiative workgroup reached consensus that improvement in UPCR, preservation of eGFR, and supportive histopathology collectively provide persuasive evidence of efficacy for complement-targeted therapies in C3G. Mechanistic plausibility, regulatory precedent, prospective trial experience, and robust cohort data support the use of these outcomes as appropriate surrogate endpoints for evaluating new therapies in C3G, although real-world variability in measurement should be considered when applying clinical trial data.

Patient-Reported Outcomes in C3 Glomerulopathy

Individuals with C3G experience a distinctive symptom burden that generic CKD instruments often miss. Qualitative and survey work shows pervasive fatigue with associated sleep disturbance and anxiety; in an international survey, more than 90% reported frequent fatigue-related symptoms, with broad effects on daily functioning and social participation, while anxiety/depression (~74%) and pain/discomfort (~65%) were also common. ¹¹⁰ Patient advocacy perspectives have emphasized the need for disease-specific measures. ¹¹¹

Recent trials have begun to operationalize this guidance: Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT Fatigue) was a prespecified secondary endpoint in APPEAR-C3G, although no statistically significant (P = .9310) change was observed with iptacopan vs placebo.^17,109 Complementary patient-reported outcome measures that capture illness uncertainty and anxiety, common in rare diseases where patients must live with limited evidence and no established therapy, can quantify this burden alongside biomarker change. Established instruments that can capture illness uncertainty and anxiety include the Mishel Uncertainty in Illness Scale (MUIS), the Patient-Reported Outcomes Measurement Information System (PROMIS), and the Fear of Progression Questionnaire (FoP-Q short forms such as FoP-Q-SF/FoP-Q-12).^112-114

Ongoing reports from these programs should clarify how biomarker improvements align with patient-perceived benefits, helping to ensure that therapeutic gains are clinically meaningful to those with lived experience.

Patient Perspectives on Living With C3 Glomerulopathy: Journey of Uncertainty, Resilience, and Hope

To better understand the real-world challenges and needs in C3G care, we explored the perspectives of two individuals living with C3G.

For M.K., hospitalization for a “routine” bout of pneumonia during childhood led to test results revealing a very rare and far more serious chronic condition called C3G. “I didn’t know what it meant at the time, just that something with my kidneys wasn’t right,” M.K. recalls. P.W.’s C3G journey took a very different path. For most of his early adulthood, he lived with a diagnosis, by exclusion, of idiopathic MPGN. His condition was only accurately reclassified as C3G after transferring to a clinic specializing in glomerulonephritis.

For both M.K. and P.W., managing C3G has been a challenging and unpredictable journey. There is no standardized treatment plan, only a shifting sequence of medications and iterative treatment approaches. “I was on a lot of different medications, which were often changing every appointment,” M.K. recalls. P.W. describes a trial-and-error approach that felt experimental, “we don’t have good evidence, but we’ll try throwing things at it and maybe something sticks.” Prednisone helped his proteinuria, but at a cost—nights with only a few hours of sleep, and each course harder to bear than the last.

Life with C3G demands constant planning. M.K. recalls that attending the necessary appointments often meant missing school or special events. As an adult, medications, dietary restrictions, bloodwork, and biweekly infusions continue to take up time and energy, yet she stays committed: “It’s difficult to do all of the things they prescribe, but I know it’s necessary to preserve my health.” P.W. cooks every meal himself, carefully avoiding excess sodium.

For individuals living with C3G, the heaviest weight may be the unknown. P.W. describes the uncertainty he felt as a teenager stepping into university life, “there are enough challenges at that time without having a disease that may derail everything in the next decade.” M.K. has carried the possibility of a transplant for years, trying to stay positive but never quite free from the fear of what is ahead. Stigma adds to the emotional toll; P.W. recalls being told, “I don’t want to be with somebody who’s broken.” He chooses to see it as early honesty rather than rejection, but the sting lingers.

Despite the challenges, both hold on to hope. New targeted treatments bring a sense of possibility. M.K. says simply, “anything that could help improve the outlook of my disease would be great.” P.W. imagines a future where early diagnosis and disease-specific therapy can keep patients off dialysis, “even delaying it by 5, 10, 20 years, there’s huge value in that.” They also know that innovation must be matched with access. Expensive drugs are of little use if patients cannot afford them. “It’s going to be important to have them on provincial formularies,” P.W. notes.

For both, the core message to health care providers is simple: listen. Ask about quality of life, relationships, mental health, and side effects. “Listen to the patient experience and what they’re going through,” M.K. says, because behind every lab result is a person, living with the realities of C3G, and holding on to the hope that the future might be different.

Future Directions

Summary of Unmet Needs in C3 Glomerulopathy

The C3G clinical landscape is rapidly evolving. However, significant unmet needs and unanswered clinical questions remain. Although biomarkers may not always translate into patient-important outcomes at the individual level, biomarkers are central to improving diagnosis, monitoring, and treatment selection, but current tools are limited (eg, heterogeneity in serum C3 levels ¹³ reduces their reliability as diagnostic or prognostic indicators). There is a critical need for the development of standardized biomarker panels and equitable access to these tools across Canadian centers to support earlier and more accurate diagnosis.

These limitations directly shape the patient experience. Individuals with C3G often face delays in obtaining an accurate diagnosis, limited treatment options, and difficulties accessing specialized care. C3 glomerulopathy predominantly affects individuals <40 years, with a mean age in the VALIANT and APPEAR trials of 26 and 27.9 years, respectively.^1,17,115 These challenges contribute to increased illness, reduced quality and length of life, and substantial financial burdens for families, the health care system, and the broader economy. ¹¹⁶

C3 glomerulopathy faces gaps in clinical trial data that further complicate treatment decisions. Emerging evidence suggests that early intervention with complement-targeted therapies may alter disease trajectory, including in the post-transplant setting, where recurrence of C3G remains a major concern, as evidenced by disease recurrence in 89% of patients at a median of 33 days post-transplantation.^16,17,56,117 As complement-directed therapies move closer to approval, a coordinated approach is required to ensure timely and equitable access across jurisdictions and patient populations in Canada.

Implementation Challenges in Canada

The approval of iptacopan and pegcetacoplan in Canada for C3G will represent a significant milestone for nephrologists and patients. This will mark the first time individuals with C3G will have access to therapies specifically designed to address the pathophysiology of their condition. The implementation of these treatments may present several challenges. In addition to the potentially elevated costs, especially in the absence of federal funding, both therapies require ongoing long-term management. Patients will need vaccination against encapsulated bacteria, yet the long-term infectious risks associated with these therapies remain unclear, warranting further investigation. There are also uncertainties surrounding the duration of treatment and long-term outcomes, particularly the effects of discontinuing treatment. Longitudinal studies are required to address these outstanding questions. ¹¹⁸ These factors also underscore the importance of careful consideration, as these therapies are integrated into clinical practice, but with governmental funding, there is hope that these challenges can be addressed, ensuring broader access and improved long-term outcomes for patients.

Limitations

We conducted a narrative review of the diagnosis and management of C3G through an expert-led process involving discussion among the authors. A formal systematic review of the literature was not undertaken, and the possibility for bias based on the authors’ own clinical experiences may have occurred. No framework (eg, Grading of Recommendations, Assessment, Development, and Evaluations (GRADE )) was used to assess the quality of evidence. ¹¹⁹ The suggestions in this review are based on the current available evidence, of which head-to-head clinical trials are lacking.

Conclusion

This review summarizes current approaches and future directions in the diagnosis and management of C3G, highlighting ongoing challenges and unmet needs in this ultra-rare kidney disease. While there has been progress with complement-directed therapies, which offer targeted, disease-modifying potential gaps remain in timely diagnosis, equitable treatment access, and real-world implementation. Better biomarkers to guide diagnosis and predict disease progression are also needed. By focusing on these areas, there is hope for advancing care and better supporting individuals with C3G.