INTRODUCTION
Over the past decade, there has been substantial progress in understanding glomerular diseases, accompanied by the emergence of several novel therapies that have reshaped their management. Despite these advances, our understanding of complement-mediated pathogenesis remains incomplete. The complement system is inherently complex, and although molecularly targeted therapies have been developed based on identified pathogenic pathways, their success in preventing or treating recurrent complement-mediated glomerular diseases has been only partial. This underscores the evolving nature of our knowledge and the need for continued investigation.
Glomerular diseases represent the second most common cause of graft loss after rejection and have a significant impact on long-term allograft survival, as demonstrated in multiple studies, including those by El-Zoghby et al[1], Briganti et al[2], Redondo-Pachón et al[3], Bomback and Appel[4], and others. They also constitute one of the leading causes of kidney failure, ranking as the third most common indication for kidney transplantation in the United States[5-9]. A review published in Nature Clinical Practice Nephrology by Ivanyi[10] further notes that recurrent glomerulonephritis is the third most important cause of renal allograft loss at 10 years post-transplantation. The resulting proteinuria and decline in graft function are associated with increased cardiovascular morbidity and mortality. Post-transplant glomerular diseases may be donor-derived, recipient-derived, de novo, or a combination of these mechanisms.
In this review, the primary focus is on recipient-derived and de novo glomerular diseases. Among these, as indicated by Figure 1 C3 glomerulopathy (C3G) has the highest reported recurrence rate, ranging from 30% to 89% across various studies. Other glomerular diseases with notable recurrence rates include focal segmental glomerulosclerosis (30%-60%), membranous nephropathy (30%-40%), membranoproliferative glomerulonephritis (MPGN; 27%-65%), and IgA nephropathy (9%-61%)[7,10-14]. It should be noted that these percentages are derived from heterogeneous study cohorts and should be interpreted as approximate estimates. Additionally, in a strict pathological sense, C3 glomerulonephritis (C3GN) is considered a subtype within the broader spectrum of MPGN.
Figure 1 Recurrence of glomerular diseases.
FSGS: Focal segmental glomerulosclerosis.
The aim of this review is to examine recurrent glomerular diseases after kidney transplantation, with particular emphasis on the frequency and risk of occurrence or recurrence of complement mediated disorders, especially C3G. The review also highlights the similarities and distinctions between C3G in native kidneys and in transplanted kidneys.
Hariharan et al[15] reported that the highest relative risks (RRs) of graft failure were observed in hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP; RR = 5.36), MPGN type II (RR = 2.77), and focal segmental glomerulosclerosis (RR = 2.25), based on an analysis of 4913 renal transplants[4,15,16]. Notably, both HUS/TTP and MPGN are characterized by complement dysregulation, attributable to either genetic variants or acquired abnormalities affecting components of the complement system[4,17]. Distinguishing between glomerular diseases driven primarily by complement overactivation and those caused by complement dysregulation remains challenging[16,18], as these mechanisms frequently overlap and often coexist within the same disease process (Figure 2). Much of our current understanding of complement-mediated glomerulonephritis has emerged from insights gained into the pathogenesis of HUS/TTP and MPGN.
Figure 2 Overlap between complement over activation and dysregulation.
C3G: C3 glomerulopathy.
ROLE OF COMPLEMENT IN KIDNEY DISEASES, PARTICULARLY C3G
C3G is a rare glomerular disease driven by fluid-phase dysregulation or abnormal activation of the alternative complement pathway. This dysregulation results in excessive deposition of C3 breakdown products within the glomeruli, ultimately triggering immune-mediated injury to the filtration barrier and leading to clinical manifestations such as proteinuria and hematuria[16,18-21].
The complement system is a critical component of innate immunity and serves as an essential bridge to the adaptive immune response. Complement proteins circulate in the bloodstream as inactive precursors and become activated upon encountering pathogens or immune complexes. Activation initiates a tightly regulated enzymatic cascade that promotes pathogen opsonization, direct cell lysis, and recruitment of inflammatory cells to sites of infection[22-24].
More than 30 complement proteins participate in this system, many of which are zymogens requiring proteolytic activation. Complement activation can occur through three distinct pathways - the classical, lectin, and alternative pathways - all of which converge on a common terminal pathway. This shared cascade culminates in membrane attack complex (MAC) formation, enhanced phagocytosis, and modulation of the broader immune response[16,24,25].
In the context of kidney disease, particularly C3G, dysregulation of the alternative pathway plays a central pathogenic role. Genetic or acquired abnormalities affecting complement regulatory proteins, convertases, or autoantibodies can lead to persistent complement activation, driving progressive glomerular injury (Figure 3).
Figure 3 Pathways of complement activation and inhibitors.
MBL: Mannose-binding lectin; MASP: Mannose-binding lectin-associated serine protease; C5aR: C5a receptor.
Complement proteins have been identified in renal biopsies across virtually all forms of glomerulonephritis, and activation of each of the three complement pathways has been documented in different kidney diseases[26,27].
In this review, the focus is on the alternative pathway of complement activation (Figure 3). Uniquely, the alternative pathway undergoes continuous low-grade activation in the fluid phase through spontaneous C3 hydrolysis, resulting in the steady generation of small amounts of C3b that can deposit on cell surfaces. Under normal physiological conditions, host cells are protected from complement-mediated injury by a network of regulatory proteins - both membrane-bound and soluble - that tightly control this baseline activation[22]. The equilibrium between complement activators and regulators is therefore critical, and disruption of this balance forms the fundamental pathogenic basis of C3G.
The complement cascade
The classical pathway of complement activation is initiated when C1q binds to an antibody-antigen complex, leading to sequential activation of C1r and C1s. These enzymes cleave C2 and C4 into their respective fragments (C2a, C2b and C4a, C4b). The resulting C4b and C2a fragments then assemble to form C4b2a, the classical pathway C3 convertase (Figure 3)[22].
The lectin pathway is activated when mannose-binding lectin recognizes pathogen-associated molecular patterns. This pathway also leads to cleavage of C2 and C4 in a manner analogous to the classical pathway, ultimately generating the same C3 convertase, C4b2a[28-31].
In contrast, the alternative pathway is continuously and spontaneously activated at a low level through the hydrolysis of C3. Under normal conditions, this baseline activation is tightly regulated by complement regulatory proteins that prevent excessive complement activity on host tissues[22,32]. The alternative pathway generates C3b at a steady, low rate. When regulation is impaired - either due to deficiency of regulatory proteins or excessive activation - C3b binds factor B, which is then cleaved by factor D into Ba and Bb. The C3b-Bb complex constitutes the initial alternative pathway C3 convertase[25]. Properdin (factor P) stabilizes this complex, amplifying complement activation[33-35].
C3a, generated during C3 cleavage, functions as an anaphylatoxin, promoting leukocyte recruitment and increasing vascular permeability[28,36]. Additional Bb fragments facilitate formation of the C5 convertase (C3BbC3b or C4b2aC3b), which cleaves C5 into C5a and C5b. C3a and C5a together act as potent anaphylatoxins, driving sustained leukocyte recruitment and inflammation[37].
C5b initiates assembly of the terminal complement complex by sequentially binding C6, C7, C8, and multiple C9 molecules to form the C5b-9 MAC. The MAC inserts into cell membranes, creating pores that disrupt osmotic balance and ultimately lead to cell lysis[38-40].
Regulation of complement activation
Beyond the classical pathway - which is triggered by antigen-antibody interactions - the alternative pathway remains in a perpetual state of low-grade activity, often described as a continuous “tick-over” driven by spontaneous C3 hydrolysis. This baseline activation allows the system to respond rapidly when the balance between complement activation and regulation shifts in favor of amplification, such as during pathogen exposure[41]. Despite this readiness, the alternative pathway is tightly controlled by a broad network of regulators of complement activations (RCAs) that prevent inadvertent injury to host tissues[38,40,42,43].
Among the most important regulators are complement factor H (CFH) and the CFH-related proteins (CFHRs), which play a pivotal role in maintaining complement homeostasis at the glomerular level. Additional key membrane-bound RCAs include membrane cofactor protein (or CD46) and decay-accelerating factor (or CD55). These regulatory proteins are expressed on glomerular endothelial and epithelial surfaces, where they act as critical checkpoints to limit complement activation and protect host cells from complement-mediated injury[43-47].
When the alternative pathway is activated, these membrane-bound RCAs rapidly engage to inactivate deposited C3b, accelerate decay of C3 convertases, and prevent propagation of the amplification loop (Figure 4). Failure or insufficiency of these regulatory mechanisms - whether due to genetic variants, autoantibodies, or acquired deficiencies - permits uncontrolled complement activation, a central pathogenic feature of C3G[43,48].
Figure 4 Alternate pathway: Activators and regulators.
MCP: Membrane cofactor protein; DAF: Decay-accelerating factor.
PATHOLOGY OF RCA
Dysfunction of complement regulatory proteins - whether due to genetic abnormalities or acquired factors - can lead to uncontrolled activation of the alternative complement pathway. Such dysregulation is central to the pathogenesis of C3G and contributes to both native disease and post-transplant recurrence (Figures 3 and 4).
Genetic abnormalities in complement regulatory factors
Multiple genes involved in the alternative complement pathway have been implicated in C3G, including C3, complement factor B, complement factor I, CFH, CD46 (membrane cofactor protein), diacylglycerol kinase epsilon, thrombomodulin, properdin, and the CFHRs (CFHR1, CFHR2, CFHR3, CFHR4A, CFHR4B)[43,49,50]. The precise contribution of these genetic abnormalities to native C3G vs recurrent disease in the allograft remains uncertain. Studies by Caravaca-Fontán et al[51] and Golshayan et al[52] suggest that pathogenic variants may be identified in approximately 20%-30% of recurrent C3G after transplant cases.
Importantly, multiple mutations may coexist within the same individual, complicating efforts to predict disease onset or recurrence. The clinical significance of variants of uncertain significance (VUS) also remains unclear. Mutations in CFHR genes, particularly those associated with CFHR nephropathy (also known as Cypriot familial nephritis), as described by Gale et al[53] and Athanasiou et al[54], exemplify how CFHR dysfunction can lead to unrestrained alternative pathway activation[55].
Given these uncertainties, current guidelines do not support routine genetic testing as part of the standard pre-transplant evaluation for C3G. Both the American Society of Transplantation and Kidney Disease: Improving Global Outcomes note that available evidence is insufficient to determine whether genetic testing provides reliable prognostic information to guide transplant candidacy or predict recurrence[43,56-58].
Certain recipient human leukocyte antigen (HLA) haplotypes have also been associated with increased recurrence risk in MPGN type I and possibly C3G, including HLA-DQA1*05:01, DQB1*02:01, and HLA-B8-DR3, as reported by Afolabi et al[59]. However, the magnitude of this association remains undefined.
Acquired factors influencing complement regulation
Acquired autoantibodies targeting complement regulatory proteins - collectively known as nephritic factors - represent another important mechanism of complement dysregulation. The most common are C3 nephritic factor (C3NeF) and C5 nephritic factor (C5NeF)[60,61]. These autoantibodies have been documented in both native and recurrent C3G after transplant[42,61]. Elevated levels of C3NeF or C5NeF correlate with low serum C3 and increased circulating MAC levels, as described by Bomback and Appel[4], Smith et al[21], and Hauer et al[62].
Less commonly, autoantibodies against CFH and complement factor B are detected. Although these have been studied more extensively in atypical HUS (aHUS), several reports - including those by Imamura et al[63] and Licht et al[64] - have identified them in subsets of C3G patients[65]. Kumar et al[66] reported anti-CFH antibodies in 17% of recurrent dense deposit disease (DDD) and 25% of recurrent C3G after transplant cases.
Mechanistically, C3NeF stabilizes the C3 convertase (C3bBb), prolonging its half-life and driving persistent alternative pathway activation. C5NeF similarly stabilizes the C5 convertase, promoting excessive formation of the terminal complement complex (C5b-9), which can damage glomerular cells and propagate inflammation[43,58,67-69].
Monoclonal gammopathy is another recognized contributor to complement dysregulation. In a study of 95 patients with C3G, Ravindran et al[70] found that C3NeF was the most common autoantibody, although some patients also harbored CFH or CFHR genetic abnormalities[47]. The therapeutic implications of this association are discussed in a later section.
Operative and surgical factors influencing C3G development post-transplant
Peri-transplant factors such as severe ischemia-reperfusion injury (IRI) and delayed graft function (DGF) can also precipitate or exacerbate complement activation. Cellular stress and inflammation associated with IRI can trigger excessive activation of the alternative pathway, creating a permissive environment for C3G recurrence - particularly in patients with underlying genetic or acquired complement abnormalities[12,19].
DGF, a known risk factor for C3G recurrence, further amplifies complement activation. When these surgical stressors occur in the context of impaired complement regulation, the alternative pathway can rapidly become overactive, leading to glomerular endothelial injury, hematuria, proteinuria, and subendothelial deposits. These findings were highlighted in the work of Garg et al[71].
Miscellaneous and other risk factors for C3G
In addition to genetic, acquired, and peri-operative contributors to complement dysregulation, several other conditions can influence the development or recurrence of C3G in the native kidney and the allograft.
aHUS: Although aHUS and C3G are distinct complement-mediated diseases, both arise from dysregulation of the alternative complement pathway and may show C3 deposition on kidney biopsy. In aHUS, complement activation occurs predominantly on cell surfaces, leading to systemic endothelial injury, thrombotic microangiopathy, and ischemic organ damage. In contrast, C3G is driven by fluid-phase complement dysregulation, resulting in dominant C3 deposition within the glomeruli and chronic glomerular injury in native kidneys and allografts. These mechanistic distinctions have been emphasized in studies by Bajwa et al[72], and Goodship et al[73].
Transplant glomerulopathy with C3 deposition: Transplant glomerulopathy accompanied by C3 deposition carries a significantly higher risk of allograft failure compared with transplant glomerulopathy lacking C3 deposits. This suggests that complement activation and C3 deposition serve as independent risk factors for graft loss, regardless of the underlying etiology[74].
Distinguishing C3G from post-infectious glomerulonephritis: C3G may closely resemble post-infectious glomerulonephritis (PIGN) histologically, making differentiation challenging. In PIGN, alternative pathway activation is triggered by immune complexes, often accompanied by transient autoantibodies to factor B, resulting in low serum C3 and elevated C5b-9 levels. Currently, no single biomarker reliably distinguishes the two conditions. However, persistent hypocomplementemia beyond 3-4 months favors C3G over PIGN. This concept is equally applicable to kidney allografts as well. Al-Ghaithi et al[75] demonstrated this overlap in a pediatric cohort: Among children initially diagnosed with PIGN between 1985 and 2010, eight were later reclassified as C3G based on modern criteria, suggesting that PIGN and C3G may represent points along a disease spectrum. Wada et al[76] further highlighted the clinical and pathological similarities and differences between these entities.
Viral triggers - cytomegalovirus and coronavirus disease 2019: Viral infections such as cytomegalovirus (CMV) and coronavirus disease 2019 can directly or indirectly activate the complement system, potentially triggering or exacerbating C3G. In such cases, management must prioritize treatment of the underlying viral process, as intensifying immunosuppression may worsen viral replication and jeopardize graft survival. Daneshgar et al[77] reported that coronavirus disease 2019 can precipitate superimposed immune complex-mediated glomerulonephritis with an MPGN pattern and cryoglobulinemia in transplant recipients, contributing to graft dysfunction. Active CMV infection may also serve as a “second hit” in predisposed renal allograft recipients. Some CMV-associated glomerulonephritis shows dense complement deposits mimicking C3G, although CMV-related injury typically includes both C3 and immunoglobulin deposition. In contrast, C3 dominance remains the defining feature of C3G. CMV infection and C3G are both significant complications in transplant recipients, and antiviral therapy may be necessary to mitigate complement dysregulation in affected patients[78,79].
Monoclonal gammopathy and paraprotein-related C3G: Monoclonal gammopathy is an increasingly recognized contributor to C3G pathogenesis. Vivarelli et al[58]. recommend screening all patients over age 50 with C3G for monoclonal gammopathy, given the high recurrence rate and the tendency for early and aggressive post-transplant relapse. Johnson et al[80] described a case of monoclonal gammopathy of renal significance causing C3G through monoclonal IgG-κ-mediated inhibition of CFH. Monoclonal immunoglobulins can impair complement regulation by: (1) Acting as anti-CFH antibodies; (2) Functioning as C3NeFs; or (3) Exerting inhibitory effects simply through high circulating concentrations[81]. Pronase digestion is essential when monoclonal immunoglobulin-related C3G is suspected, as it can unmask hidden paraproteins. Treating the underlying plasma-cell disorder may be therapeutic for C3G itself[82], as demonstrated in multiple studies, including those by Sethi et al[83] and Coltoff et al[84], where myeloma-directed therapy (e.g., daratumumab) led to meaningful clinical improvement. This holds true for recurrent C3G after kidney transplant.
HISTOPATHOLOGY OF C3G: NATIVE KIDNEY VS TRANSPLANTED KIDNEY
C3G encompasses two major subtypes - DDD and C3GN - which share overlapping clinical and histopathological features, suggesting a continuum rather than entirely distinct disease entities[21]. On light microscopy, findings are heterogeneous. A membranoproliferative pattern is most commonly observed, although mesangial hypercellularity, endocapillary proliferation, and even crescent formation may be present[11,85].
Native kidney pathology
Immunofluorescence and electron microscopy are essential for distinguishing DDD from C3GN. C3GN typically shows waxy, ill-defined, weakly electron-dense deposits, often located in the mesangium and along capillary walls. DDD, in contrast, is characterized by highly electron-dense intramembranous deposits, including classic “sausage-shaped” or ring-like structures within the lamina densa of the glomerular basement membrane[86,87].
Dominant C3 staining on immunofluorescence - at least two orders of intensity greater than any immunoglobulin or C1q - is a diagnostic requirement for both entities. C1q is consistently negative, underscoring the central role of the alternative complement pathway.
Recurrent C3G after transplant in the allograft
Although recurrent C3G in the transplant shares the same diagnostic criteria as native disease, several differences are notable: (1) C3 staining is often subtler, appearing focal or segmental rather than the diffuse, global pattern typical of native C3G; (2) Some cases show isolated C3 deposition, while others demonstrate C3 with IgG, though C1q remains negative; and (3) In recurrent DDD, the classic highly dense intramembranous deposits may be less prominent, with many cases showing waxy, ill-defined deposits resembling C3GN. These changes may persist on protocol biopsies 1-2 years post-transplant[11,86-88].
These observations support the hypothesis that DDD and C3GN may represent different morphologic expressions or stages of a shared disease process, although additional biopsy-based studies are needed to confirm this[11].
Role of histologic scoring in prognosis
Caravaca-Fontán et al[51], in a multicenter cohort of 111 patients from the Spanish GLOSEN network, proposed and validated the C3G histologic index (C3G-HI), incorporating activity and chronicity scores. When correlated with clinical variables such as 24-hour proteinuria and immunosuppressive treatment, only the chronicity score emerged as an independent predictor of kidney failure. Tarragón et al[11] reinforced these findings in a smaller cohort, noting that while activity scores remained relatively stable early in the disease course, chronicity scores progressed steadily, reflecting irreversible injury even before overt clinical deterioration.
These findings highlight the importance of early protocol biopsies post-transplant to detect subclinical recurrence, allowing intervention before significant chronic damage accumulates[11,89].
Prognostic differences between C3GN and DDD
Despite shared mechanisms and overlapping histology, the two subtypes differ markedly in long-term outcomes after transplantation. Reported recurrence rates are: C3GN: 70%-90%; DDD: 90%-100%. These high recurrence rates underscore the aggressive nature of complement-mediated injury in the allograft and the need for vigilant monitoring and early detection[2,15,90].
Therapeutic considerations for C3G: A review within a review
Management of C3G after renal transplantation remains challenging because current induction and maintenance immunosuppressive regimens do not specifically target complement activation or its regulatory pathways. As a result, therapeutic strategies are largely extrapolated from observational data, mechanistic insights, and small cohort studies rather than robust clinical trials.
Preventive and pre-transplant considerations
At present, the benefit of genetic screening for C3G - either before or after transplantation - remains uncertain. No major guidelines recommend routine genetic testing for transplant candidates or donors, largely because: (1) The prognostic significance of many complement gene variants is unclear; (2) VUS are common; and (3) The combined effect of donor and recipient variants on recurrence risk is unknown.
Similarly, there is no definitive evidence that living donor transplantation reduces recurrence risk compared with deceased donor transplantation. However, living donor kidneys are associated with less IRI and lower rates of DGF - both of which are known triggers of complement activation[91,92]. This theoretical advantage has led some clinicians to favor living donation when feasible, though data remain inconclusive.
Screening living donors for complement gene variants is also controversial. The presence of VUS in either donor or recipient complicates interpretation, and the clinical impact of combined genetic backgrounds is not yet understood.
Immunosuppression strategies and endothelial protection
Some studies have proposed that maintenance immunosuppression with belatacept or mammalian target of rapamycin inhibitors may offer endothelial protection and potentially mitigate complement activation. This approach aims to avoid the synergistic endothelial stress caused by calcineurin inhibitors in patients with underlying complement dysregulation. Ongoing clinical investigations (e.g., NCT06291077) are exploring this strategy, but its long-term efficacy remains unknown[93,94].
Role of protocol biopsies
Because standard immunosuppressive regimens do not directly target complement abnormalities, the utility of protocol biopsies specifically for detecting complement dysregulation is unclear. Nevertheless, early histologic detection of subclinical recurrence - particularly rising chronicity scores - may be valuable, as suggested by recent studies. However, no formal guidelines currently recommend protocol biopsies solely for complement-related surveillance.
TREATMENT APPROACH: GENERAL AND TRANSPLANT SPECIFIC ASPECTS
Overview of C3G and conservative management approaches
C3G was first described in 2007 and is now recognized as a complement-mediated glomerular disease driven by dysregulated activation of the alternative complement pathway[95]. This dysregulation may arise from genetic variants in complement pathway genes, autoantibodies targeting complement components, or a combination of both. Despite these shared mechanisms, C3G represents a heterogeneous disease spectrum with complex triggers and variable clinical behavior. The disease is typically progressive and demonstrates inconsistent responses to conventional immunosuppressive therapy after kidney transplantation[70].
Conservative management
All patients with C3G should receive renin-angiotensin-aldosterone system (RAAS) inhibition to reduce proteinuria, control blood pressure, and mitigate cardiovascular risk. RAAS blockade should be individualized, as not all patients tolerate aggressive blood pressure lowering. Importantly, RAAS inhibition should not be viewed as definitive therapy; rather, it serves as supportive management while the underlying complement dysregulation remains the primary therapeutic target.
An intriguing mechanistic insight emerged from the work of Békássy et al[96], who demonstrated that renin can cleave C3 into C3a and C3b, mimicking the activity of C3 convertase[97,98]. This renin-mediated cleavage was inhibited by the direct renin inhibitor aliskiren (Figure 5). In vitro and in vivo studies showed that aliskiren reduced systemic and renal complement activation, including: (1) Increased serum C3; (2) Decreased C3a and C5a; (3) Reduced renal C3 and C5b-9 deposition; and (4) Decreased glomerular basement membrane thickening.
Figure 5 Treatment approach to C3 glomerulopathy.
C3G: C3 glomerulopathy; RAAS: Renin-angiotensin-aldosterone system; MMF: Mycophenolate mofetil; ACTH: Adrenocorticotropic hormone.
These findings were observed in three pediatric patients with dense deposit disease followed for four to seven years[96-98]. The authors proposed that renin-mediated complement activation may help explain the renal tropism of complement-mediated injury, particularly in individuals with complement gene mutations or autoantibodies. They suggested that aliskiren may be considered in selected patients without ongoing renal function decline, though broader clinical validation is still needed[97]. The role of aliskiren in post-transplant recurrence of C3G has not yet been studied and represents a promising area for future investigation.
Non-specific immunosuppression
Most kidney transplant recipients receive a standard triple-drug maintenance regimen consisting of tacrolimus, mycophenolate mofetil (MMF), and prednisone. Among these, MMF and corticosteroids have been the most extensively studied in native C3G[99-102]. Although some patients demonstrate partial improvement, recurrence still occurs despite adequate immunosuppression, underscoring that these therapies do not address the underlying complement dysregulation (Figure 5).
The mechanism by which MMF may reduce disease activity in C3G is not fully understood. It is hypothesized that MMF decreases intraglomerular inflammation, thereby attenuating downstream injury[103]. However, recurrent C3G in the transplant often represents a more aggressive phenotype, and responses to MMF-based and steroid-based regimens have been inconsistent and generally disappointing.
A Spanish multicenter study of 97 patients (81 with C3GN and 16 with DDD) reported better outcomes with MMF plus corticosteroids compared with other immunosuppressive strategies such as rituximab or steroids alone. Nevertheless, the regimen was not curative, and many patients ultimately progressed to graft failure, highlighting the need for more targeted therapies[101].
Overall, non-specific immunosuppression post-transplant may provide partial benefit but does not reliably prevent recurrence or halt disease progression. Effective therapy must ultimately target the complement pathway itself, the central driver of C3G.
Targeted immunosuppression: “Complimenting the complement”
The unique microenvironment of the glomerulus predisposes it to complement-mediated injury. The polyanionic glycomatrix of the glomerular basement membrane (GBM), combined with: (1) High local concentrations of complement proteins (due to ultrafiltration and hemoconcentration); (2) local complement synthesis by tubular epithelial cells; and (3) the fenestrated nature of glomerular endothelial cells (leaving approximately 40% of the surface area devoid of membrane-bound complement regulators), creates a setting in which even subtle defects in alternative pathway regulation can lead to pronounced complement deposition and inflammation (Figure 5)[18,104].
C5 inhibition - eculizumab: The past decade has seen the emergence of complement-directed therapies, beginning with eculizumab, a monoclonal antibody that blocks C5 activation. Initially developed for paroxysmal nocturnal hemoglobinuria (PNH), eculizumab has shown variable but sometimes encouraging results in both native and recurrent C3G after transplant. Bomback et al[105] reported improved kidney function, reduced proteinuria, and decreased MAC levels in several patients treated with eculizumab, though relapse occurred upon discontinuation[106-108]. Regunathan-Shenk et al[109] observed mixed outcomes: 4 of 7 patients responded, while 3 progressed to graft failure. Gurkan et al[106] noted partial benefit in patients with C3NeF-positive disease. Collectively, these studies suggest that C5 blockade alone is insufficient for many patients, particularly when the primary defect lies upstream in the alternative pathway.
Plasma exchange: Plasma exchange has been used to reduce circulating autoantibodies (e.g., anti-CFH) or nephritic factors. While some case reports describe benefit - especially in rapidly progressive disease or early post-transplant recurrence - the overall response is incomplete and inconsistent. Plasma exchange may help select patients but is not a reliable standalone therapy for C3G.
Rituximab: Rituximab depletes B cells and can reduce autoantibody production, but its role in C3G is limited and phenotype-specific. In cases driven by autoantibodies (e.g., C3NeF, monoclonal gammopathy-associated C3G), rituximab may be beneficial. A few case reports describe complete remission in C3NeF-positive patients[110]. However, most C3G - especially genetically mediated disease - does not respond reliably to rituximab. Post-transplant use has shown mixed results, with occasional benefit in monoclonal gammopathy-associated C3G but no consistent graft salvage. Given that C3G is fundamentally a complement-driven disease, therapies directly targeting complement activation (e.g., eculizumab, iptacopan) are generally more mechanistically aligned.
Adrenocorticotropic hormone-based therapies: Adrenocorticotropic hormone (ACTH) (repository corticotropin) has been explored in small studies and case reports. Zand et al[111] described its use in C3G, and Naseer et al[112] reported improvement in de novo C3GN when ACTH was combined with eculizumab. ACTH acts via the melanocortin-1 receptor on podocytes, which is upregulated during podocyte injury[113]. However, ACTH does not target complement dysregulation, its effects are largely limited to proteinuria reduction, and evidence in transplant recipients is extremely limited. There is no strong evidence supporting ACTH as a primary therapy for C3G.
NOVEL COMPLEMENT-TARGETING THERAPIES
Much of the therapeutic landscape for C3G has been shaped by the foundational work of Bomback and colleagues. Several emerging agents target different components of the complement cascade, reflecting a shift toward mechanism-based therapy (Figure 5).
Inhibitors of C5 and the terminal complement pathway
Therapies targeting C5 or the terminal complement pathway were initially developed for aHUS and PNH. Their application in C3G is logical but biologically limited, as C3G originates upstream of C5 activation.
Eculizumab: Eculizumab, a monoclonal antibody that prevents cleavage of C5 into C5a and C5b, was one of the earliest complement inhibitors evaluated in C3G. Although early reports suggested improvement in kidney function, proteinuria, and circulating MAC levels, subsequent studies demonstrated inconsistent and often incomplete responses, with frequent relapses after discontinuation[70,114]. This is equally applicable for native kidney and renal allografts[70]. The fundamental limitation is mechanistic: Eculizumab blocks terminal complement activation, but does not inhibit C3 convertase, nor does it prevent ongoing C3 deposition in the glomeruli. Thus, inflammation driven by C3a (anaphylatoxin) and C3b (opsonin) persists despite C5 blockade. Nevertheless, eculizumab remains an important therapeutic option and has been used in transplant recipients with variable success[19,115].
Ravulizumab: Ravulizumab is a long-acting, humanized monoclonal antibody that targets the same C5 epitope as eculizumab but offers a significantly extended dosing interval (every 8 weeks vs every 2 weeks). Phase 3 trials in aHUS demonstrated robust TMA resolution, improved renal function, and dialysis independence[116-119]. Although currently approved only for aHUS, ravulizumab is being explored as a second-line or investigational therapy in other complement-mediated diseases, including IgA nephropathy and lupus nephritis. Evidence in C3G - particularly post-transplant recurrence - is limited and mixed, similar to eculizumab. Both eculizumab and ravulizumab effectively block terminal complement activation but do not address upstream alternative pathway dysregulation, which is central to C3G pathogenesis. Their role in recurrent C3G after transplant remains investigational.
C5a receptor blockade - avacopan (CCX168): Avacopan is an orally administered small-molecule antagonist of the C5a receptor. By blocking receptor engagement rather than C5 cleavage, avacopan inhibits: C5a-mediated vascular permeability, oxidative burst, pro-inflammatory cytokine release, and chemotaxis of myeloid and lymphoid cells. The ACCOLADE trial (phase 2, 2024) evaluated avacopan in 57 patients with C3G. Key findings included: The primary endpoint (C3G-HI activity score) did not reach statistical significance. However, avacopan significantly slowed fibrosis progression, reflected by improved C3G-HI chronicity scores. Avacopan produced a statistically significant improvement in epidermal growth factor receptor (eGFR) compared with placebo. The drug was safe and well tolerated. These results suggest that avacopan may help slow chronic injury and preserve renal function, even if it does not fully suppress upstream complement activation. Discussions with regulatory agencies are ongoing regarding potential approval pathways. Avacopan is currently Food and Drug Administration (FDA)-approved for ANCA-associated vasculitis, but its role in C3G - particularly in transplant recipients - remains investigational.
Factor B and factor D inhibitors
Iptacopan (fabhalta): Iptacopan is a first-in-class, orally administered factor B inhibitor that selectively blocks the formation of the alternative pathway C3 convertase. By preventing the cleavage of Factor B into Ba and Bb, iptacopan: Halts formation of C3 convertase (C3bBb), prevents downstream C5 convertase formation, interrupts the amplification loop of the alternative pathway, reduces C3 deposition in the glomeruli, and preserves the classical and lectin pathways. This proximal, pathway-specific mechanism directly targets the core defect in C3G. APPEAR-C3G Trial and FDA approval: The APPEAR-C3G phase III trial demonstrated that iptacopan significantly improves clinical and histologic outcomes in adults with C3G. Based on these results, the FDA approved fabhalta (iptacopan) in March 2025 as the first and only approved therapy for C3G. Key findings from the randomized, double-blind, placebo-controlled trial include: (1) Rapid and sustained reduction in proteinuria: A 35.1% reduction at 6 months, improvement seen as early as day 14; (2) Stabilization of kidney function: Improved eGFR slope compared with historical decline, more patients achieved a composite renal endpoint (stable eGFR + ≥ 50% proteinuria reduction); (3) Reduction in complement deposition: Follow-up biopsies showed significant decreases in glomerular C3 deposits; (4) Favorable safety profile: Well tolerated over 12 months, most adverse events were mild to moderate, and requires risk evaluation and mitigation strategy enrollment due to infection risk from encapsulated bacteria. The APPEAR-C3G trial represents a major therapeutic breakthrough for this ultra-rare disease, offering the first targeted therapy that addresses the root cause of C3G rather than its downstream consequences; and (5) Use in transplant recipients: Emerging case reports and early clinical experience suggest that iptacopan may: Reduce proteinuria, improve allograft function, and normalize complement activity in patients with recurrent C3G after kidney transplantation[120,121]. Although transplant-specific data remain limited, iptacopan is rapidly becoming the new standard of care for both native and recurrent C3G after transplant.
Ruxoprubart (NM8074): Ruxoprubart is a humanized monoclonal antibody designed to selectively inhibit the alternative complement pathway by binding to Bb, the active component of the C3 convertase (C3bBb). By blocking Bb’s catalytic activity, ruxoprubart prevents formation of both C3 and C5 convertases while sparing the classical pathway. A phase Ib/IIa open-label, dose-escalation study is currently evaluating: Safety. Efficacy, and immunogenicity in adults with C3G. The FDA has granted Investigational New Drug approval for NM8074 for multiple complement-mediated diseases, including PNH, aHUS, and IgA nephropathy. The planned NM8074-C3G-101 study includes: (1) 18 patients, with potential expansion; (2) Three dose cohorts (5 mg/kg, 10 mg/kg, 20 mg/kg); (3) Escalation to higher doses only after safety review of the preceding cohort; and (4) To date, no studies have evaluated ruxoprubart in post-transplant C3G.
Danicopan: Danicopan (formerly ALXN2040/ACH-4471) is an orally administered factor D inhibitor. Factor D is a serine protease essential for the activation of factor B, which is cleaved into Ba and Bb during alternative pathway activation. The Bb fragment binds C3b to form the C3 convertase (C3bBb), the central amplification engine of the alternative complement pathway. By inhibiting factor D, danicopan prevents the formation of C3 convertase and thereby reduces alternative pathway-mediated C3 fragment deposition. This mechanism has shown clear benefit in PNH, where danicopan reduces extravascular hemolysis. However, two clinical trials in C3G failed to demonstrate consistent therapeutic benefit, and the drug did not advance in this indication. Danicopan received orphan drug designation from the FDA in 2017 for PNH and is approved as an add-on therapy to ravulizumab or eculizumab for extravascular hemolysis. Transplant-specific data remain limited, though ongoing studies are evaluating danicopan for recurrent C3G after kidney transplantation. Early signals suggest possible reductions in proteinuria and stabilization of graft function, but definitive evidence is still lacking.
Lampalizumab: Lampalizumab is an antibody-based factor D inhibitor initially developed for geographic atrophy in age-related macular degeneration. Despite early promise, phase III trials in age-related macular degeneration were unsuccessful, and lampalizumab has not progressed to clinical trials in C3G. It has not been evaluated in the setting of recurrent C3G after kidney transplantation.
Pelecopan (BCX9930): BCX9930 is an oral small-molecule factor D inhibitor, designed to block the formation of the alternative pathway C3 convertase. A phase 1 open-label study demonstrated: (1) Rapid and potent suppression of alternative pathway activity (> 99%); (2) Sustained inhibition for 24 hours after a single 600 mg dose; and (3) These encouraging results supported further development. The phase 2 RENEW study (NCT05162066) was initiated to evaluate longer-term use in C3G and other renal diseases. However: In April 2022, the FDA placed a partial clinical hold due to elevated serum creatinine in PNH patients. Although the hold was later lifted with a revised dosing protocol, BioCryst (NC, United States) terminated development of BCX9930 in December 2022, citing commercial non-competitiveness and safety-related dosing limitations. Patients benefiting from BCX9930 were transitioned to the company’s next-generation factor D inhibitor, BCX10013. There is no published literature evaluating BCX9930 in recurrent C3G after kidney transplantation.
Recombinant factor H
For patients with genetic or autoimmune factor H deficiency, replacement therapy with recombinant factor H represents an appealing therapeutic strategy. A moss-based recombinant factor H product, CPV-104, is currently in early-phase development[122]. Clinical trials are planned, but as of now, no significant clinical data exist, and the agent has not been evaluated in post-transplant C3G.
C3 inhibition
Pegcetacoplan: Pegcetacoplan is a Polyethylene glycolated derivative of the compstatin family - small cyclic peptides that bind to C3 and prevent its cleavage[123]. As a C3 inhibitor, pegcetacoplan blocks activation of all three complement pathways (classical, lectin, and alternative) at the level of C3, thereby preventing downstream formation of C3a, C3b, C5 convertase, and the MAC[124]. Pegcetacoplan is approved in the United States and Europe for PNH and geographic atrophy. In August 2025, the FDA expanded its approval to include adults and adolescents (≥ 12 years) with C3G or primary immune complex-MPGN, including those with recurrent disease after kidney transplantation[124]. Its efficacy has been demonstrated in both native and post-transplant C3G. Some of the highlights from the VALIANT and NOBLE trials are mentioned here. VALIANT trial (phase 3 - native C3G): The VALIANT trial evaluated pegcetacoplan in adults and adolescents with native C3G. VALIANT (NCT05067127) is the largest trial ever conducted in C3G and immune complex-MPGN. It is a randomized, double-blind, placebo-controlled, multicenter study enrolling 124 patients aged ≥ 12 years, including both native and post-transplant cases. Participants received 1080 mg pegcetacoplan or placebo twice weekly for 26 weeks, followed by a 26-week open-label extension. The primary endpoint was the log-transformed urine protein-to-creatinine ratio at week 26. Key findings included: (1) 68.3% reduction in proteinuria at 26 weeks compared with placebo; (2) 71% of patients achieved complete clearance of C3c deposits; (3) Stabilization of eGFR, indicating preservation of kidney function; and (4) Significant reduction in C3c staining intensity on biopsy, reflecting decreased complement deposition. These results established pegcetacoplan as a highly effective therapy for native C3G. NOBLE (phase 2) and VALIANT (phase 3) – post-transplant C3G: C3G frequently recurs in kidney allografts, often leading to graft loss. Both the NOBLE and VALIANT studies evaluated pegcetacoplan in recurrent C3G after transplant: (1) Reduced proteinuria; (2) Stabilized eGFR; (3) Some patients achieved complete clearance of C3c deposits; (4) Decreased C3G histologic activity scores; and (5) Reduced glomerular inflammation and complement deposition. These findings suggest pegcetacoplan is effective in both preventing and treating recurrence in the allograft. Safety profiles of pegcetacoplan indicates that it was well tolerated in both native and transplant populations: (1) No serious treatment-related adverse events in phase 2; (2) No graft loss or rejection attributable to the drug; and (3) Most common side effects: Injection-site reactions, headache, respiratory infections. All participants completing VALIANT have entered the VALE long-term extension study.
ARO-C3 (NCT05083364): ARO-C3 is an RNA interference therapeutic designed to silence hepatic production of C3, thereby reducing activation of all complement pathways. The phase 1/2 trial (AROC3-1001) evaluated ARO-C3 in healthy volunteers and patients with complement-mediated kidney diseases, including C3G and IgA nephropathy. Key findings: (1) In healthy volunteers: 88% mean reduction in serum C3, 91% reduction in AH50, indicating strong suppression of alternative pathway activity; and (2) In IgA nephropathy patients (part 2): Up to 89% reduction in C3, 41% reduction in proteinuria by week 24. Safety: Generally well tolerated; no serious adverse events or treatment discontinuations; mild headaches and injection-site reactions were the most common side effects. Although promising, ARO-C3 has not yet been studied in recurrent C3G after kidney transplantation.
AMY-101: AMY-101 is a next-generation compstatin-based inhibitor that directly targets C3, blocking all three complement activation pathways. It has received orphan drug designation from both the FDA and European Medicines Agency for C3G, reflecting its potential to address a major unmet need. To date, no published data exist regarding its use in post-transplant C3G, and clinical development remains in early stages.
Dual C3 and C5 inhibition
KP104 (NCT05517980): KP104 is a first-in-class bifunctional fusion protein combining: A humanized anti-C5 monoclonal antibody, and a regulatory domain derived from factor H. This dual-action design allows KP104 to inhibit both C3-driven amplification and C5-mediated terminal pathway activation, offering a more comprehensive blockade than single-target agents. KP104 is currently in phase 2 clinical trials for C3G and other complement-mediated diseases. The NCT05517980 study is evaluating its safety and efficacy, but no data are yet available regarding its use in post-transplant C3G.
Lectin pathway inhibition and C3G
The lectin pathway is an important arm of the innate immune system that, unlike the classical pathway, does not require antibodies for activation. It is initiated when pattern-recognition molecules - such as mannose-binding lectin or ficolins - bind to carbohydrate motifs on microbial surfaces or damaged host cells. This binding activates mannose-binding lectin-associated serine proteases (MASPs), particularly MASP-2, which cleave C4 and C2 to form the lectin pathway C3 convertase (C4bC2b)[125-128]. This enzyme cleaves C3 and feeds into the central complement cascade, amplifying inflammation and tissue injury (Figure 5).
Role of the lectin pathway in C3G: Although alternative pathway dysregulation is the hallmark of C3G, emerging evidence suggests that the lectin pathway may contribute in a subset of cases: Some patients exhibit C4 nephritic factors, autoantibodies that stabilize the lectin pathway C3 convertase. MASP-1 and MASP-3 can activate components of the alternative pathway, creating cross-talk between the lectin pathway and alternative pathway. Lectin pathway activation has been implicated in other complement-mediated glomerular diseases, such as IgA nephropathy[129]. Thus, while lectin pathway activation is not the primary driver of C3G, it may amplify complement dysregulation in select phenotypes.
Lectin pathway inhibition in C3G: Most therapeutic development in C3G has focused on alternative pathway inhibition, given its central pathogenic role. However, lectin pathway-targeted therapies may be relevant in patients with demonstrable lectin pathway activation or C4 nephritic factors.
Narsoplimab (OMS721): Narsoplimab is a monoclonal antibody that selectively inhibits MASP-2, the key enzyme responsible for lectin pathway activation. It has shown promise in IgA nephropathy, where lectin pathway activation is well established. Early clinical trials in C3G (NCT05855083, NCT02682407) have been conducted, but results have not yet been widely reported. At present: Narsoplimab is not approved for C3G. There is no evidence supporting its use in recurrent C3G after kidney transplantation. Because alternative pathway dysregulation is the core abnormality in C3G, lectin pathway inhibitors are unlikely to replace alternative pathway-targeted therapies but may eventually serve as adjunctive options in select cases.
CONCLUSION
C3G is a rare but clinically significant complement-mediated kidney disease with high recurrence rates after kidney transplantation, often resulting in premature allograft loss. The disease arises from uncontrolled activation of the alternative complement pathway, leading to progressive glomerular injury manifested by hematuria, proteinuria, and eventual decline in glomerular filtration rate.
Post-transplant recurrence is common - sometimes occurring within months - and requires vigilant surveillance. Because the clinical presentation may lag behind histologic injury, protocol biopsies play a crucial role in early detection. Although most centers perform these at six months, the frequent observation of early, subclinical recurrence suggests that earlier biopsies (as early as three months) may be beneficial, though further studies are needed to define optimal timing.
Management of recurrent C3G after transplant remains challenging. Traditional immunosuppression does not address the underlying complement dysregulation, and untreated recurrence carries a poor prognosis. The emergence of complement-targeted therapies - including C5 inhibitors (eculizumab), C3 inhibitors (pegcetacoplan), and factor B inhibitors (iptacopan) - has transformed the therapeutic landscape. Early intervention with these agents has shown promise in stabilizing kidney function, reducing proteinuria, and improving graft survival. However, the optimal treatment strategy continues to evolve as our understanding of complement biology deepens.
Effective care requires multidisciplinary collaboration among nephrologists, transplant specialists, pathologists, and genetic counselors. Comprehensive evaluation - including genetic testing, autoantibody profiling, and complement biomarker assessment - will be essential as precision medicine becomes increasingly central to C3G management.
Despite recent advances, no consensus guidelines from Kidney Disease: Improving Global Outcomes or major transplant societies currently outline standardized diagnostic or therapeutic protocols for C3G in transplant recipients. Continued research is urgently needed to refine surveillance strategies, identify reliable biomarkers, and determine long-term outcomes of complement inhibition, including the implications of lifelong therapy. C3G remains a complex and evolving disease entity, but the rapid development of targeted complement therapeutics offers renewed hope for improving outcomes in both native and transplanted kidneys.
