Recurrence of C3 Glomerulopathy and Immune Complex–Mediated Membranoproliferative Glomerulonephritis After Kidney Transplantation: Challenges and Opportunities

Abstract

Recurrent C3 glomerulopathy (C3G) and primary immune complex–mediated membranoproliferative glomerulonephritis (IC-MPGN) remain major causes of kidney allograft dysfunction and loss. Their pathogenesis involves genetic susceptibility, acquired complement dysregulation, and transplant-related triggers, yet no clear validated predictors of recurrence exist. Recurrence rates after kidney transplantation frequently exceed 60% and are associated with progression to graft failure. Early detection, often achievable through protocol biopsies, offers an opportunity for timely intervention, although histologic recognition of early recurrence can be challenging. Comprehensive pretransplant evaluation, including genetic and molecular complement testing and screening for monoclonal gammopathies, may refine risk stratification. Conventional treatments, including intensified immunosuppression, rituximab, and plasma exchange, have shown limited and inconsistent efficacy. Conversely, complement-targeted therapies have yielded promising outcomes. Although eculizumab remains the most extensively studied agent, emerging proximal complement inhibitors such as iptacopan and pegcetacoplan have shown encouraging efficacy in both native and recurrent disease. However, optimal timing, prophylactic use, and long-term safety in transplant recipients remain uncertain. In this review, we outline the clinical spectrum, key diagnostic and therapeutic challenges, and emerging treatment strategies for recurrent C3G and IC-MPGN, highlighting advances that may ultimately improve graft survival and patient outcomes.

C3G is an ultrarare glomerular disease driven by dysregulation of the alternative complement pathway.^1,2 This aberrant activation leads to the deposition of C3 and its breakdown products within the glomeruli, triggering inflammation and progressive decline in kidney function.³

C3G is currently defined by dominant C3 staining on immunofluorescence of kidney biopsy, either in isolation or markedly exceeding other immune reactants by ≥ 2 orders of magnitude.⁴ Electron microscopy further distinguishes C3G into 2 main subtypes: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD).^5,6 Emerging evidence suggests that dysregulation of the complement system may play a pathogenic role in cases diagnosed as primary IC-MPGN, where C3 and Ig deposits are present at similar intensities and no underlying systemic disease is identified.^7,8 Notably, in some patients, a first kidney biopsy may show features typical of primary IC-MPGN, whereas a subsequent biopsy reveals findings consistent with C3G.^7,8 This shift is thought to reflect transient activation of the classical complement pathway at the time of diagnosis, possibly triggered by infections, though the underlying mechanisms remain incompletely understood. Moreover, complement genetic variants and/or circulating autoantibodies against complement components have been detected in a subset of IC-MPGN cases, supporting a mechanistic overlap with C3G and further suggesting that IC-MPGN may lie within the same disease spectrum.^9,10

Despite significant advances in the understanding of C3G/IC-MPGN in recent years, the overall prognosis remains poor, with up to 30% to 50% of adult patients progressing to kidney failure^9,11, 12, 13, 14 and profoundly affecting the lives of patients and their families.¹⁵ Kidney transplantation is the preferred treatment for kidney failure and, given the relatively young age at onset and the rapid progression of these conditions, many patients are listed for transplantation.¹⁶ However, disease recurrence remains a major clinical challenge, leading to graft loss in approximately 50% of patients.16, 17, 18, 19

In this review, we explore the clinical heterogeneity, major challenges, and uncertainties associated with recurrent C3G and primary IC-MPGN. In addition, we examine the evolving therapeutic landscape, highlighting recent advances that hold promise for improving patient outcomes in these complex and often progressive conditions.

Recurrence Rates and Natural History

The natural history of disease recurrence in kidney allografts remains poorly characterized, although it typically exhibits a slowly progressive course, characterized by gradual estimated glomerular filtration rate (eGFR) decline accompanied by progressive increases in proteinuria levels (Figure 1). This knowledge gap largely stems from the limited availability of high-quality data, because most existing evidence is derived from small, single-center studies or retrospective cohort analyses spanning extended time periods, during which C3G was not yet recognized as a distinct clinical and pathological entity.^16,18 In Table 1,16, 17, 18, 19, 20, 21, 22, 23, 24 we present a summary of the main findings from retrospective studies examining the recurrence of C3G or primary IC-MPGN following kidney transplantation.

Figure 1.

Schematic representation of recurrent disease pathogenesis, illustrating hyperactivation of the alternative complement pathway and subsequent glomerular deposition. The figure depicts the potential longitudinal evolution of clinical parameters (eGFR, proteinuria, and hematuria) in response to progressive accumulation of C3 molecules and their degradation fragments within the kidney allograft. C3G, C3 glomerulopathy; eGFR, estimated glomerular filtration rate; IC-MPGN, immune complex–mediated membranoproliferative glomerulonephritis; RBC, red blood cell.

Table 1.

Summary of case series and retrospective studies examining the recurrence of C3G or primary IC-MPGN following kidney transplantation

Author (yr)	Zand et al.17	Wong et al.20	Regunathan-Shenk et al.19	Frangou et al.21	Kumar et al.22	Caravaca-Fontán et al.18.	Tarragón et al.23.	Patry et al.24.	Halfon et al.16.
Number of patients (type)	21 (C3GN)	8 (C3GN)	19 (12 C3GN /7 DDD)	17 (CFHR5 nephropathy)	21 (12 C3GN /9 DDD)	166 (34 C3G / 132 IC-MPGN)	18 (12 C3GN / 6 DDD)	20 (12 C3GN /5 DDD / 3 IC-MPGN)	41 (31 C3G / 10 IC-MPGN)
Before kidney transplantation
Age at KTx, yrs	36 (IQR 12–69)	34 (IQR 21–55)	28 (IQR 23–41)	48 (IQR 32–64)	31 (IQR 16–60)	47 (IQR 38–60) C3G 43 (IQR 33–55) IC-MPGN	31 (IQR 28–35)	13.8 ± 3.9	34 ± 15 C3G 53 ± 13 IC-MPGN
Time from diagnosis to KTx or dialysis, mos	62 (IQR 0–400)	–	48 (IQR 0–190) C3GN 37 (IQR 3–118) DDD	–	< 1–34	60 (IQR 14–115) C3G	–	–	–
Type of donor, n	LD: 11 DD: 3	LD: 2 DD: 6	LD: 14 DD: 5	LD: 6 DD: 11	LD: 17 DD: 4	LD: 0 / 9 DD: 34 / 123	LD: 13 DD: 5	LD: 6 DD: 14	LD: 22 DD: 19
Complement genetic variants	–	All with hybrid CFHR3-1	3/10 (MCP, CFHR5, CFI)	All with duplication of exons 2-3 in CFHR5	At least one CFH gene variant present in 93%	10 out of 34 tested (CFH, C3, CFB, CFHR5)	6 out of 12 tested (CFH, MCP, CFHR5)	6 out of 16 tested (C3, CFI, CFH)	3 out of 7 tested (CFHR1, CFHR3)
Antibodies against complement components	–	–	8/10 (C3NeF, C5NeF predominant)	–	None	4 (12%) C3Nef	3 out of 9 tested (C3Nef, C4Nef, C5Nef)	10 out of 16 tested (C3Nef, antiFH)	–
Paraprotein, n (%)	3 (21)	–	3/7 (MGUS)	1 (6)	None	None	0 out of 11 tested	–	–
Anti-complement therapy	None	None	–	–	–	–	–	7 (35)	–
After kidney transplantation
Recurrence rate, n (%)	14 (66.7)	4 (50)	10 (83) C3GN 6 (86) DDD	12 (71): only 3 (17) histologically confirmed	5 (42) C3GN 6 (67) DDD	21 (62) C3G 20 (15) IC-MPGN	16 (89)	8 (66) C3GN; 2 (40) DDD; 1 (33) IC-MPGN	4 (13) C3G; 3 (30) IC-MPGN
Time to recurrence, mos	28	< 1 - 101	14 (IQR 0-80) C3GN 15 (IQR 2-32) DDD	164 (IQR 9 – 207)	< 1–27	14 (IQR 3 – 81) C3G 30 (IQR 11 – 68) IC-MPGN	<1: 33 days (IQR 13-141)	<1 - 12	14 (IQR 5-20)
Graft loss, n (%)	7 (33)	4 (50)	3 (25) C3GN 6 (86) DDD	5 (29)	8 (38)	14 (41) C3G 45 (34) IC-MPGN	–	6 (30)	6 (15)
SCr, mg/dl / eGFR, ml/min per 1.73 m2	1.6 / –	0.7-1.5 / 43 – >60	– / –	– / –	1,2–5 / –	– / 30 (16-41)	– / 42 (20-58)	– / –	1.3 (1.1–1.5) / –
Proteinuria, g/d	0.79 (0.22-4.3)	–	–	2.5 (1–5.8)	1.8 (0.9–2.7)	3.2 (2–6.6)	In 5 patients (27%) < 1 g: 258 mg/g	–	2 (1–2.5)
Hematuria, n (%)	6 (43)	–	–	All with graft loss	–	–	7 (38)	–	6 (14)
Serum C3 levels, mg/dl	–	–	–	Normal (median 98)	Low: 100% (C3GN) / 89% (DDD)	60 (52-64) C3G –	Low in 4 out 11 tested (36%)	Ranging from low to normal levels	Low in 3 out of 6 tested
Histopathologic findings, n (%)			Including retransplantation	Performed in 3	C3GN / DDD	C3G / IC-MPGN
Mesangial proliferative pattern	8 (57)	–	10 (43)	–	8 (66) / 8 (88)	18 (53) / –	12 (75)	–	–
Membranoproliferative pattern	6 (43)	4 (100)	6 (26)	–	–	17 (50) / –	None
C3 staining (2-3+)	14 (100)	–	18 (78)	–	12 (100) / 9 (100)	12 (35) / –	8 (50)
IgG or IgM staining (1-2+)	5 (36)	–	8 (35)	–	3 (25) / 2 (22)	–	–
Mesangial or Subendothelial EDD	12 (85)	Both	16 (70)	3 (100)	12 (100) / 2 (22)	–	14 (88) and 6 (38)
Treatment received, n (%)						C3G / IC-MPGN
No additional treatment	10 (71)	4 (100)	–	–	–	–	–	–	–
Rituximab	3 (21.4)	0	3 (16)	–	–	4 (19) / 4 (20)	–	None	1 (2)
PLEX	1 (7)	0	4 (21)	2 (12)	4 (19)	3 (14) / 3 (15)	–	2 (10)	1 (2)
Immunosuppression uptitration	1 (7)	0	–	2 (12)	–	4 (19) / 6 (30)	–	–	1 (2)
Eculizumab	0	0	7 (37)	–	–	9 (43) / None	2 (Eculizumab) / 2 (other anticomplement drug)	12 (60)	3 (7)

C3GN, C3 glomerulonephritis; DD, deceased donation; DDD: dense deposit disease; EDD, electron dense deposits; eGFR, estimated glomerular filtration rate; IC-MPGN, immune complex–mediated membranoproliferative glomerulonephritis; IQR, interquartile range; KTx, kidney transplantation; LD, living donation; MGUS, monoclonal gammopathy of unknown significance; PLEX, plasma exchange; SCr, serum creatinine.

Reported recurrence rates vary widely, ranging from 67% to 89% for C3G and 15% to 45% for IC-MPGN.16, 17, 18, 19, 20, 21, 22, 23^,25, 26, 27, 28 Variability in reported incidence is likely influenced by differences in biopsy practices (e.g., protocol vs. indication biopsies) and significant heterogeneity in follow-up duration across studies. Nevertheless, controversy persists regarding the definition of recurrent C3G or IC-MPGN; specifically, whether isolated C3 deposition on immunofluorescence is sufficient to define early recurrence, or if histological lesions (e.g., mesangial proliferation or other glomerular changes) are also required.

In the case of IC-MPGN, these figures often reflect its classification as a histologic pattern rather than a distinct clinical entity, making the true recurrence rate of primary IC-MPGN less well-defined. Notably, registry data consistently demonstrates that the MPGN pattern of injury commonly observed in C3G and primary IC-MPGN is associated with a higher risk of death-censored graft failure because of recurrent glomerulonephritis, both overall and among recipients with specific primary glomerulonephritis diagnoses.²⁹ Nevertheless, it remains essential to investigate the underlying etiology of MPGN (e.g., monoclonal gammopathies, chronic infections, or systemic autoimmune diseases).¹⁸ A retrospective study conducted in Spain examined posttransplant MPGN recurrence using the current classification system.¹⁸ Among 220 kidney transplant recipients with MPGN, 186 (84%) had IC-MPGN, of whom 132 (70%) were classified as idiopathic and 34 (16%) had complement-mediated MPGN. Recurrence was more frequent in patients with dysproteinemia (67%) and complement-mediated MPGN (62%) and tended to occur earlier in these groups (median of 14 and 7 months, respectively).¹⁸ In contrast, the lowest recurrence rate was observed in patients with idiopathic MPGN (15%). These findings underscore the importance of a thorough and systematic evaluation for secondary causes whenever an MPGN pattern is identified on biopsy.

In the case of C3G recurrence, rates appear comparable between DDD and C3GN, as well as in patients with pediatric-onset disease.17, 18, 19^,23,24,30 A recent study by a Columbia University group reported an even higher recurrence rate of 89%, with a median time-to-recurrence of approximately 1 month after transplantation.²³ Notably, the study detected lower proteinuria at recurrence (258 mg/g) and higher recurrence rates than other studies, likely because of protocol biopsies conducted at 6, 12, and 24 months. This suggests that disease recurrence may have been underestimated in the literature and underscores the insidious nature of the disease, with subclinical recurrences often progressing to chronicity before clinical detection.²³

Regarding clinical presentation, IC-MPGN recurrence tends to manifest more frequently with overt clinical signs, including nephrotic-range proteinuria.¹⁸ Nevertheless, proteinuria and microscopic hematuria remain the most prevalent markers of disease recurrence in both conditions.16, 17, 18^,21,30 Notably, in certain familial forms of C3GN such as CFHR5 nephropathy, 1 study suggested that increased proteinuria levels and a greater frequency of hematuria were associated with graft loss following recurrence, reflecting increased disease activity.²¹

Once recurrence occurs, the prognosis is poor for both conditions. Reported graft loss rates range from 50% to 60% for C3G and 43% to 56% for IC-MPGN, typically within 14 to 40 months of recurrence diagnosis.²⁶ This rapid progression underscores the aggressive nature of these diseases in transplant settings. Key predictors of poor outcomes include early recurrence (< 15 months posttransplant), an eGFR < 30 ml/min per 1.73 m², and serum albumin levels < 3.5 g/dl at the time of recurrence.¹⁸

Risk Factors for Recurrence

Classic studies have identified both donor- and recipient-related factors as determinants of disease recurrence. Living donor transplantation has been suggested to be associated with a higher risk of recurrence, possibly reflecting shared genetic predisposition between donor and recipient²⁸ and/or the fact that it is often performed preemptively, when the disease may still be active; however, findings across studies remain inconsistent. From a pathophysiological perspective, infections and ischemia-reperfusion injuries, particularly those linked to prolonged cold ischemia times in deceased donor transplantation, may activate the alternative complement pathway,³¹ thereby acting as potential triggers for posttransplant C3G recurrence.³² Despite these considerations, living donor transplantation is not currently contraindicated in patients with C3G or primary IC-MPGN. Other studies have identified young age at disease diagnosis,³³ high-level proteinuria,³⁴ low serum C3 levels,³⁵ and preemptive transplantation²⁸ as potential predictors of recurrence, possibly because of heightened disease activity at the time of transplantation. A similar rationale is observed at the histopathological level, where the severity of glomerular damage, particularly the extent of mesangial proliferation and the presence of crescents, has been associated with an increased risk of recurrence in some studies.³⁶ However, most of these data derive from retrospective studies, thereby limiting causal inference. Despite extensive research, no risk factor, biomarker, or a combination of these reliably predicts recurrence.

Notably, although genetic mutations and acquired complement dysregulation both contribute to disease pathogenesis, neither can reliably predict recurrence risk. Nonetheless, the data remain limited and somewhat controversial, because some groups have questioned the utility of genetics in isolation for risk stratification.³⁷ The genetic landscape of C3G and IC-MPGN is characterized by overlapping features but remains highly complex and incompletely understood.^26,38 Recent conclusions from Kidney Disease: Improving Global Outcomes recommend that all patients with nonmonoclonal C3G and primary IC-MPGN should undergo genetic and molecular complement studies.³⁸ Ideally, this evaluation should be implemented in potential kidney transplant candidates as part of the pretransplant work-up, when available.

Genetic studies may identify gain-of-function pathogenic variants in C3,^39,40 or loss-of-function variants in regulatory proteins such as complement factor I (CFI)⁴¹ or complement factor H (CFH).⁴² In addition, testing for genomic rearrangements in the complement factor H-related (CFHR) gene cluster is recommended.^43,44 These rearrangements often result in the formation of fusion proteins with the ability to dysregulate the alternative complement pathway.^43,45, 46, 47 Genetic variants in CFHRs genes have been widely described as familial forms of C3G, with some showing endemic distribution in Cyprus.⁴⁵ One such example, formerly referred to as Cypriot or CFHR5 nephropathy, is caused by an internal duplication of the first 2 consensus domains of the FHR5 protein and has a reported recurrence rate of up to 45.5%.²¹ The hybrid CFHR3-1 gene also deserves special attention, because it is associated with an autosomal dominant inheritance pattern, high penetrance, and a high rate of recurrence. Studies have shown that affected families have multiple members developing C3G, often with an early onset and aggressive disease course.^20,48 Furthermore, recent findings indicate that FHR-1 proteins containing duplicated dimerization domains exhibit enhanced binding to C3-opsonized surfaces and promote complement activation via the alternative pathway.⁴⁹

MPGN is linked to other autoimmune disorders, including a notably higher prevalence of type 1 diabetes mellitus among relatives of individuals with DDD.⁵⁰ The study conducted by Levine et al.⁵¹ established an association between this primary form of MPGN and the human leukocyte antigen loci DQA1∗05:01, DQB1∗02:01, and DRB1∗03:01, whereas no correlation was found with other genes encoding components of the complement alternative pathway.

One major limitation is that genetic testing results do not always yield definitive answers, because pathogenic complement variants are only found in about 20% to 29% of C3G recurrence cases,^26,37,38 and common structural variants are not always considered risk factors for disease.⁵² Adding to the complexity, sometimes it is the combination of these rare variants with other complement mutations or acquired factors such as autoantibodies that predispose individuals to disease onset.⁵² These findings suggest that genetic predisposition alone is insufficient to explain disease onset in most cases, highlighting the multifactorial nature of pathogenesis.⁴⁴

Nonetheless, there remains a substantial amount of research to be conducted in this area, and exploring alternative methods for investigating gene expression could prove beneficial in comprehending the true pathogenesis of the disease. The study by Tarragon et al.²³ demonstrated significant differential expression using transcriptomics technology in native kidney biopsies from patients with C3G compared with other glomerular disease controls. Interestingly, most of the genes significantly expressed in native C3G did not maintain their significance when C3G recurred in transplanted kidneys, suggesting that the microenvironment and immunological context within the allograft may alter gene expression. Another approach could involve proteomics technology to precisely identify which complement proteins are affecting the glomeruli, ultimately enabling the prediction of which complement pathway should be targeted through complement inhibitors.⁵³

Acquired autoantibodies, including nephritic factors (Nefs) such as C3Nef, C5Nef, C4Nef, and anti–complement factor H, are detected in 28% to 56% of patients with C3G and 40% to 53% of those with IC-MPGN.^54,55 In addition to Nefs, other antibodies have been identified in patients with C3G, including those targeting factor H (5%–20%), factor B (< 10%), and anti-C3b (< 10%).⁴⁴ Their prevalence is particularly elevated in patients with DDD, with C3Nefs identified in 78% to 86% of cases.¹¹ This variability may be attributed to methodological challenges and well-documented fluctuations in C3Nef activity in the serum during follow-up.⁴⁴ For example, testing for alternative complement pathway activation may yield misleading results if performed during periods of immunological quiescence. Furthermore, the natural history of these antibodies has been insufficiently characterized in the literature, including whether immunosuppressive therapies can effectively target and reduce their production in transplant settings. Thus, it is tempting to speculate that patients who undergo transplantation with detectable or elevated levels of these antibodies may have a higher risk of earlier disease recurrence, as observed in other glomerulonephritis. However, whether these antibodies can inform decisions regarding transplantation timing remains uncertain, necessitating further research in this area.²⁶ This uncertainty is reinforced by the lack of standardized consensus assays, variability across testing methodologies, temporal fluctuations in autoantibody levels, and the occasional presence of complement-binding autoantibodies at low frequency in healthy individuals.⁵⁶

Finally, the association between monoclonal gammopathy of renal significance and C3G is well-documented, representing a significant risk factor for recurrence.^18,57, 58, 59 This association often results in early recurrence and rapid progression to kidney failure if left untreated. Consequently, it is recommended that patients with C3G, particularly those aged > 50 years or candidates for kidney transplantation undergo evaluation for an underlying monoclonal gammopathy.^10,38 However, data on the clinical presentation, treatment response, and outcomes of monoclonal gammopathy-associated C3G diagnosed after kidney transplantation remain very limited.^18,58,60,61 Clone-targeted therapies are considered the treatment of choice for patients with monoclonal gammopathy-associated C3G.⁵⁹ Notably, 1 study reported poor kidney outcomes in transplant recipients with monoclonal gammopathy-associated C3G, even among those who achieved a hematological response.⁵⁸ The authors speculated that the unfavorable prognosis may be attributed to the presence of irreversible chronic kidney lesions at the time of diagnosis.

Treatment Landscape

Unlike patients with native kidney disease, those with recurrent C3G or primary IC-MPGN often face more resistant disease despite immunosuppression, which poses a significant clinical challenge.¹⁸ This may, in part, reflect a selection bias: patients who progress to kidney failure and undergo transplantation are often those who exhibit poor responses to standard therapies at disease onset, suggesting either a more aggressive disease phenotype or a delayed initial diagnosis.

Interestingly, although several nonrandomized studies have described a potential benefit of corticosteroids plus mycophenolate mofetil in C3G of native kidneys,^62,63 this therapeutic strategy has not proven to be as effective among kidney transplant recipients with recurrent disease, because most of these patients receive this type of maintenance immunosuppression.^17,18 In clinical practice, the management of recurrent C3G or IC-MPGN often involves the addition of nonspecific immunosuppressive strategies such as rituximab and plasma exchange¹⁸ (Table 1). The rationale for these interventions is based on their capacity to deplete B cells, thereby reducing the production of autoantibodies, and to directly remove circulating autoantibodies and complement components. Theoretically, such approaches may offer particular benefit in disease forms mediated by autoantibodies, while providing limited efficacy in cases primarily driven by genetic abnormalities.²¹ However, published data report inconsistent outcomes, with several studies demonstrating minimal or no clinical benefit.^16,17,19,30 Moreover, these therapies are not without risk, including potential adverse events such as bleeding and excessive immunosuppression, which may predispose to opportunistic infections. Nonetheless, drawing firm conclusions from these studies is challenging because of several limitations, including small sample sizes; heterogeneity in treatment regimens, often involving multiple therapies within the same patient; and the lack of stratification according to underlying pathogenic mechanisms (genetic vs. autoimmune).

Given the underlying pathogenesis of C3G or primary IC-MPGN, complement blockade represents a more rational therapeutic approach for recurrent disease. The most extensive clinical experience to date is with the off-label use of eculizumab, a monoclonal antibody targeting C5. The first proof-of-concept evidence originated from a clinical trial involving 6 patients (3 with DDD, 3 with C3GN, 3 of them with disease recurrence in the allograft) who received eculizumab for 1 year.⁶⁴ At last follow-up, 2 patients showed significant improvement of kidney function; 1 patient achieved complete remission with partial reabsorption of deposits; 1 patient stabilized kidney function with significant improvement of mesangial and endocapillary lesions. However, the remaining cases developed progressive kidney disease. Patients with higher serum C5b-9 levels were more likely to respond to this treatment. Several reports have documented stabilization of eGFR decline and reductions in proteinuria following eculizumab administration in selected patients.⁶⁴ Notably, a meta-analysis reported the lowest allograft loss rate associated with eculizumab (33%; 95% confidence interval: 12%–57%) compared with other therapeutic options.⁶⁵ In the multicenter study by Caravaca-Fontán et al.¹⁸, eculizumab was the second most frequently used immunosuppressive agent (administered to 9 patients, 43%) following corticosteroids (10 patients, 48%) in cases of complement-mediated MPGN. Among these patients, 3 (14%) achieved partial remission, 1 with corticosteroids alone and 2 with a combination of corticosteroids, mycophenolate mofetil, and eculizumab. In addition, 2 patients (10%) achieved complete remission, including 1 who received eculizumab as monotherapy. Despite these findings, the efficacy of eculizumab has been inconsistent across studies, which aligns with its mechanism of action targeting C5 downstream in the terminal complement cascade, whereas the primary dysregulation in C3G and primary IC-MPGN occurs at the level of C3.²⁶ This highlights the need for more effective therapeutic strategies targeting the proximal complement pathway.

After years of research, several novel complement inhibitors have emerged as potential treatments for both native and recurrent forms of C3G and IC-MPGN. The development of these agents has been challenging, and some, such as danicopan^66,67 and avacopan,⁶⁸ have failed to demonstrate clear efficacy in achieving key clinical end points. Nevertheless, encouraging results have been reported with proximal complement inhibitors such as iptacopan and pegcetacoplan, and their success has culminated in regulatory approval by the US Food and Drug Administration, offering renewed optimism for the advent of targeted disease-modifying treatments (Table 2).

Table 2.

Overview of the mechanisms of action, therapeutic regimens, and potential adverse effects of currently available complement inhibitors

Complement blocker	Mechanism of action	Administration	Evidence or reported experience in kidney transplantation	Safety profile
				Potential side effects
Eculizumab (Soliris ®)	Monoclonal antibody against C5, preventing terminal complement activation and formation of the membrane attack complex (C5b-9).	Intravenous infusion. 900 mg IV weekly for 4 weeks, then 1200 mg IV every 2 weeks (same as in atypical hemolytic uremic syndrome)	Phase 1, open-label, proof of concept study. Three kidney transplant recipients (out of a total of 6) treated for 1 year. Stabilization of kidney function with mild histologic improvements Several case reports and case series with off-label use of the drug and variable results.18,19,80, 81, 82, 83, 84	Headache, leukopenia, thrombocytopenia, meningococcal infections (requires vaccination), anaphylaxis
Iptacopan (Fabhalta ®)	Oral small-molecule inhibitor of factor B, blocking formation of the C3 convertase and thereby inhibiting the alternative pathway.	Oral administration. 200 mg twice daily. Only approved for adults aged ≥ 18 yrs.	Phase 2 clinical trial69: 11 patients. Median C3 deposit score decreased by 2.50 (scale: 0–12) on day 84 vs. baseline (P = 0.03). Only 10 completed extension Phase 2 study,70 showing stable kidney function and urinary protein excretion at 12 months, but a significant increase in serum C3 levels compared with baseline. APPEAR-C3G (Phase 3 clinical trial): no kidney transplant patients. Several case reports published: 6 patients85, 86, 87, 88, 89	Upper respiratory tract infection, abdominal pain, headache, potential risk of infections because of encapsulated bacteria (requires vaccination)
Pegcetacoplan (Empaveli ®, Aspaveli ®)	C3/C3b inhibitor, blocking both alternative and classical pathways at a central level.	Subcutaneous injection. - Adults and children $\ge$ 12 years: 1080 mg twice weekly - Pediatric cases (based on weight): 30–35 kg: 540 mg twice weekly for 1 week, then 648 mg twice weekly; 35–50 kg: 648 mg 1st dose, then 810 mg twice weekly.	NOBLE trial (Phase 2 randomized clinical trial): 10 patients.74 At week 12, 5 of 10 patients (50%) receiving pegcetacoplan achieved a ≥ 2-log reduction in C3 staining VALIANT trial (Phase 3 randomized clinical trial)76: 5 kidney transplant patients randomized to pegcetacoplan vs. 4 to placebo. There was a 64.9% relative reduction in proteinuria at week 26.	Upper respiratory tract infection, injection-site reactions, nausea, headache, potential risk of infections because of encapsulated bacteria (requires vaccination)
Avacopan (Tavneos ®)	Molecule targeting C5a receptor, preventing terminal complement induced cellular activation.	Oral administration. 30 mg twice daily.	ACCOLADE trial (phase 2 randomized clinical trial)68: 1 patient randomized to avacopan vs. 1 to placebo. The primary end point for the study was not met.	Diarrhea, vomiting, headache, peripheral edema, neutropenic sepsis, pneumonia, gastroenteritis.
Danicopan (Voydeya ®)	Molecule targeting factor D, blocking the alternative pathway.	Oral administration. 200 mg 3 times a day	No published studies in transplant recipients. Optimal systemic concentrations of danicopan were not achieved	Upper respiratory tract infection, nausea, vomiting.

Iptacopan, an oral selective inhibitor of factor B, demonstrated positive results in a phase 2 open-label trial.⁶⁹ Among patients with native kidneys (n = 16), iptacopan achieved a 45% reduction in proteinuria from baseline to week 12, accompanied by a significant reduction in C3 deposits in kidney transplant recipients with recurrent disease in the allograft (n = 10). The treatment also resulted in sustained normalization of plasma C3 levels, stabilization of creatinine clearance, and improvement in eGFR slope. An extension of this study further confirmed a proteinuria reduction of up to 57% in native kidneys and an eGFR improvement of 6.8 ml/min per 1.73 m² at 12 months.⁷⁰ Recurrent C3G in post–kidney transplantation cases showed improvement in eGFR over time.⁶⁹ Stable increases in serum C3 levels and a trend toward reduced C3 deposition were observed in both cohorts, reflecting decreased alternative complement pathway activity.

These encouraging results paved the way for a phase 3 randomized controlled trial, the APPEAR-C3G study, designed to evaluate the impact of iptacopan on proteinuria and eGFR over 12 months in a larger cohort of 74 patients with C3G.⁷¹ Notably, this trial included only individuals with native kidney disease. Patients in the iptacopan arm (n = 38) experienced a 35.1% reduction in proteinuria at 6 months compared with the placebo group (n = 36).⁷² Following crossover from placebo to iptacopan, proteinuria decreased by up to 31%. Moreover, iptacopan treatment was associated with stabilization of eGFR over the 12-month study period, with the annualized eGFR slope showing improvement compared with the historical rate of decline before treatment. Importantly, iptacopan demonstrated a favorable safety profile, with no deaths, no cases of meningitis or meningococcal sepsis, and no treatment discontinuations because of treatment-emergent adverse events.⁷²

Pegcetacoplan, a subcutaneous targeted inhibitor of C3 and C3b, regulates complement overactivation at a proximal level through different mechanisms. It inhibits the activation of C3 by blocking both classical and alternative pathway C3 convertases, suppresses amplification of the complement cascade by targeting the alternative pathway C3 convertase and its feedback loop, and prevents the deposition of C3b on target surfaces.⁷³

The efficacy and safety of pegcetacoplan was specifically evaluated in a phase 2, open-label trial involving 10 kidney transplant recipients with biopsy-proven recurrent C3G in the allograft (NOBLE trial).⁷⁴ The primary end point was the reduction in C3c staining intensity on kidney biopsy at week 12 in patients treated with pegcetacoplan plus standard-of-care, compared with standard-of-care alone. At week 12, 5 of 10 patients (50%) receiving pegcetacoplan achieved a ≥ 2-log reduction in C3 staining, whereas 8 of 10 (80%) achieved a ≥ 1-log reduction. In addition, among pegcetacoplan-treated patients with baseline proteinuria ≥ 1000 mg/g, the median reduction in proteinuria was 54.4%, accompanied by stabilization of kidney function and improvements in serum complement biomarkers. These encouraging results supported the initiation of a larger phase 3 randomized controlled trial, the VALIANT study, designed to evaluate the efficacy and safety of pegcetacoplan in a broader population.⁷⁵ This trial included both adolescents and adults with either native kidney or recurrent disease, encompassing diagnoses of C3G and primary IC-MPGN. The study followed a design similar to the APPEAR-C3G trial, consisting of a 26-week double-blind period comparing pegcetacoplan plus standard-of-care versus placebo plus standard-of-care, followed by a 26-week open-label extension in which all participants received pegcetacoplan. A total of 124 patients were enrolled, with 63 randomized to the pegcetacoplan arm and 61 to placebo; 9 patients had recurrent disease in the allograft.⁷⁶ At week 26, the trial met its primary end point, demonstrating a statistically and clinically significant 68.1% reduction in proteinuria in the pegcetacoplan group compared with placebo, with differences emerging as early as week 4. Kidney function remained stable throughout the treatment period. Importantly, the reduction in proteinuria was consistent across all study subgroups, including those with recurrent disease in the allograft. Patients receiving pegcetacoplan had 31-fold higher odds of achieving a ≥ 50% reduction in proteinuria relative to placebo. In addition, 71.4% of pegcetacoplan-treated patients achieved zero-intensity C3 staining on follow-up biopsy. Pegcetacoplan was well-tolerated, with no significant infection-related adverse events reported.

These results have the potential to transform the therapeutic landscape of C3G and IC-MPGN, and it is anticipated that clinical management guidelines will be revised accordingly following the publication of the final trial outcomes.

Challenges, Uncertainties, and Potential Opportunities

Despite recent advances in the understanding and treatment of C3G and primary IC-MPGN, significant challenges and uncertainties persist in the context of recurrent disease in the allograft. The heterogeneity of underlying pathogenic mechanisms complicates risk stratification and individualized therapeutic decision-making (Figure 2). These complexities are further amplified by the unique immunological environment and inherent vulnerabilities of the transplanted kidney, which introduce additional layers of diagnostic and therapeutic uncertainty.

Figure 2.

Venn diagram summarizing areas of consensus and highlighting research gaps in recurrent C3 glomerulopathy and primary immune complex–mediated membranoproliferative glomerulonephritis, across domains of pathogenesis/risk factors, diagnosis or monitoring, and treatment or prognosis. IF, immunofluorescence.

Early diagnosis of recurrent disease is critical, and protocol kidney allograft biopsy is likely the optimal approach to achieve it. Although the timing and frequency of protocol biopsies may vary across centers, the scheme currently implemented in our institution includes biopsies at 6, 12, 24, 36, 48, and 60 months after kidney transplantation. Beyond this period, biopsies are performed only when clinically indicated. Compared with waiting to perform an indication biopsy—triggered by overt kidney dysfunction or significant urinary abnormalities—a protocol biopsy offers important advantages. In kidney transplantation, particularly with deceased-donor grafts, baseline kidney function may not be optimal, and mild proteinuria can occur as a consequence of donor characteristics, recipient factors, or immunosuppressive therapy. Thus, fluctuations in these baseline abnormalities may mask early histological changes, thereby delaying recognition of subclinical disease and hindering timely intervention.

Nonetheless, histopathologic assessment of protocol biopsies is not without challenges. The histological features of early recurrent disease often differ from those observed in advanced stages, which may lead to diagnostic uncertainty.²⁵ In native C3G, kidney biopsies frequently display an MPGN pattern of injury at diagnosis, followed by mesangial proliferative, diffuse endocapillary proliferative, or diffuse sclerosing lesions.^12,77 In contrast, recurrent C3G in the allograft more commonly exhibits mesangial proliferative or endocapillary proliferative patterns, with mesangial electron-dense deposits predominating over deposits in other glomerular compartments.^16,17,23 These observations suggest that, in the early stages of recurrence, C3 deposition and inflammation primarily originate in the mesangium before extending to other glomerular structures, ultimately progressing to chronic injury. Moreover, it is tempting to speculate that standard immunosuppressive regimens used in kidney transplantation may mitigate inflammatory activity, thereby contributing to less severe histologic lesions.¹⁰ In contrast, C3 positivity on immunofluorescence staining may sometimes be seen in nonspecific areas, leading to misinterpretation of recurrent disease. In this context, reliance on protocol biopsy findings alone carries the risk of overdiagnosis and ultimately, overtreatment, particularly when subclinical changes of uncertain clinical significance are detected.¹⁰

The advent of novel proximal complement inhibitors offers the potential to markedly alter the natural history and prognosis of recurrent disease in the kidney allograft. However, the optimal timing for initiating such therapy remains uncertain. In the authors’ view, early intervention with targeted proximal complement blockade (e.g., iptacopan, pegcetacoplan) once recurrent disease is confirmed could mitigate the risk of developing chronic, irreversible histologic lesions, thereby improving long-term graft survival. Although the natural history of recurrence in the allograft may differ from that in native kidneys, drawing parallels with the latter could provide valuable insight into the potential disease course after transplantation. Moreover, in selected patients who have lost previous grafts because of disease recurrence, prophylactic administration of proximal complement inhibitors might be a reasonable strategy to prevent further recurrences, despite the current lack of sufficient evidence to support a universal recommendation. The optimal duration of therapy in this setting is also unclear; however, considering the risk-benefit balance, a substantial proportion of patients may ultimately require lifelong treatment to maximize graft survival and, consequently, overall survival. Prospective studies are urgently needed to evaluate such strategies.

A potential concern with proximal complement inhibitors is their long-term safety in kidney transplant recipients, a population with substantial comorbidities related to chronic kidney disease and prolonged immunosuppression. Experience from their use in other conditions, such as paroxysmal nocturnal hemoglobinuria, suggests that these agents are generally well-tolerated. Recent clinical trials in complement-mediated kidney diseases have confirmed a favorable safety profile, with most adverse events being mild to moderate and only few cases requiring treatment discontinuation.69, 70, 71, 72, 73^,75,78,79 As with all complement inhibitors, strict adherence to vaccination protocols against encapsulated bacteria is essential to reduce the risk of severe infections. Looking ahead, postmarketing surveillance, long-term registries, and real-world evidence will be critical to fully characterize the safety profile of these agents in the transplant population, optimize their use, and ensure that the benefits of improved graft survival are not offset by preventable complications.

Conclusion

Recurrent C3G and primary IC-MPGN remain major causes of kidney allograft loss. Their pathogenesis reflects a complex interplay of genetic susceptibility, acquired complement dysregulation, and transplant-related triggers, yet no reliable biomarker or risk model currently predicts recurrence. Comprehensive pretransplant evaluation, including genetic and molecular complement studies and screening for monoclonal gammopathies is recommended to improve risk stratification and guide management. Targeted proximal complement inhibition has emerged as a promising strategy. Iptacopan and pegcetacoplan have demonstrated significant reductions in proteinuria, stabilization of kidney function, and histologic improvement in recent trials, including patients with recurrent disease. These agents may redefine the therapeutic landscape; however, optimal timing, treatment duration, and use in prophylaxis remain unresolved, as does their long-term safety in the transplant setting. Future priorities include multicenter studies to better characterize the natural history of recurrence, validate predictors of risk, and determine the most effective and safe use of novel complement inhibitors. Integrating precision diagnostics with mechanism-based therapies offers the best prospect of improving graft survival and long-term patient outcomes in these historically devastating conditions.

Disclosure

TC reports fees from Novartis and SOBI. MP reports fees from Alexion, GSK, Novartis, Otsuka, Sanofi, SOBI, Travere, and Vifor outside the submitted work. FC-F reports fees from Novartis, Apellis, Alexion, SOBI, Bayer, and AstraZeneca, outside the submitted work. All the other authors declared no competing interests.

Funding

Work in this study was supported by the Instituto de Salud Carlos III (ISCIII), project PI24/00140, and co-funded by the European Union. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the funding institutions.