Version July 2025
INTRODUCTION —
The C3 glomerulopathies are a group of rare forms of glomerulonephritis characterized by dysregulation of the alternative complement pathway, which results in predominant C3 deposition within the glomeruli. The clinical presentation is variable, and the diagnosis is made by immunofluorescence examination of a kidney biopsy specimen, supplemented by studies of the complement system. Whenever possible, the pathogenic mechanism should be identified as this can help guide therapy.
Patients with C3 glomerulopathy commonly progress to end-stage kidney disease (ESKD) and require kidney replacement therapy, including dialysis and/or transplantation. Among such patients who undergo transplantation, recurrence is common in the transplanted kidney.
This topic reviews recurrent C3 glomerulopathy in the transplanted kidney. The recurrence in the transplanted kidney of idiopathic MPGN is discussed elsewhere. (See "Membranoproliferative glomerulonephritis: Recurrence of idiopathic disease after transplantation".)
The presentation, classification, causes, and treatment of MPGN in the native kidney are discussed elsewhere:
●(See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)
●(See "Membranoproliferative glomerulonephritis: Treatment and prognosis".)
●(See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis".)
CLASSIFICATION AND PATHOGENESIS —
C3 glomerulopathy includes two subtypes that are defined by structural characteristics observed on electron microscopy (EM); these are called dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) [1]. Both subtypes are caused by excessive activation of the alternative complement pathway, which results either from loss of function of one of the complement regulatory proteins (factor H or factor I) [1-4] or from gain-of-function mutations in C3 that lead to resistance to regulation by factor H. A genetic etiology is identified in approximately 10 to 20 percent of patients, most commonly in the genes encoding complement factor H (CFH), complement factor I (CFI), C3, or complement factor B (CFB) [5]. A more common cause of C3 glomerulopathy is an acquired factor, known as nephritic factor, which is identified in approximately 50 to 80 percent of patients. A nephritic factor is an autoantibody that stabilizes the convertase. As an example, a C3 nephritic factor binds to and stabilizes the C3 convertase (an enzyme that converts C3 to C3b). (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Pathogenesis'.)
C3 glomerulopathies have been reported in association with monoclonal gammopathies, particularly in older patients (typically >50 years old). It is speculated that monoclonal immunoglobulins can function like nephritic factors and impair complement regulation.
The classification and characteristic histologic features of subtypes are described in depth elsewhere. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Classification based upon immunofluorescence microscopy'.)
EPIDEMIOLOGY AND RISK FACTORS —
The reported recurrence rate of C3 glomerulonephritis (C3GN) is greater than 50 percent [6-14]. The recurrence rate of dense deposit disease (DDD) is much higher and approaches approximately 80 to 100 percent [13-15]. Recurrence after transplantation occurs earlier and is more aggressive if associated with monoclonal gammopathy [14,15]. Other factors associated with an increased risk of recurrence include low complement levels, persistently elevated levels of nephritic factors, and rapid progression to end-stage kidney disease (ESKD) in the native kidneys [16].
CLINICAL PRESENTATION —
Patients with recurrent C3 glomerulopathy can present within weeks to months following transplantation [13,14]. The clinical manifestations are the same among patients with dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) and include some or all of the following: proteinuria, hematuria, increased creatinine, and/or hypocomplementemia [13,14]. The degree of proteinuria is variable. In one study of 14 patients with recurrent C3GN, protein excretion ranged from 22 to 4288 mg per day [14]. Six patients in this series had hematuria, and, among 11 patients with available data, 5 had low serum C3 levels.
Some patients may have long-standing mild and stable kidney function impairment and/or proteinuria. Others have a subacute/chronic progressive course with slowly deteriorating kidney function. A minority of patients (around 8 percent in C3 glomerulopathy) experience acute, rapidly progressing deterioration of their kidney function. The exact relative frequency of these different forms is not known.
DIAGNOSIS AND EVALUATION —
The diagnosis of recurrent C3 glomerulopathy is strongly suspected when patients with known dense deposit disease (DDD) or C3 glomerulonephritis (C3GN) in the native kidney present with proteinuria, hematuria, or a decline in estimated glomerular filtration rate (eGFR). The diagnosis is made by kidney biopsy. A biopsy with analysis of tissue by light microscopy, immunofluorescence, and electron microscopy should be performed in all transplant recipients who have either DDD or C3GN as a cause of end-stage kidney disease (ESKD) in the native kidney and who present with unexplained new or worsening proteinuria, hematuria, or a decline in eGFR. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Pathology and pathogenesis'.)
The histologic features that characterize the disease are discussed elsewhere. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Diagnosis and evaluation'.)
An evaluation of the alternative complement pathway should be performed in patients after a histologic diagnosis of C3 glomerulopathy is obtained to define the underlying etiology of disease. Similarly, this should be performed among patients who have a histologic diagnosis of recurrent C3 glomerulopathy, if this has not been done previously. This evaluation is described separately. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Establishing the diagnosis'.)
Among patients who have a known complement abnormality, an extensive re-evaluation is not necessary.
TREATMENT —
At this time, there are no controlled studies on which to base therapeutic recommendations for recurrent C3 glomerulopathy [17]. Several drugs targeting the proximal complement pathway are under investigation in clinical trials. (See 'Investigational therapies' below.)
Approach to therapy — Our approach to treatment is based upon the severity of the presentation.
●Mild disease – If proteinuria is <1.5 g/day and the estimated glomerular filtration rate (eGFR) is stable, we treat with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). This is based upon the observed benefit of these agents in nontransplant recipients with proteinuric kidney disease; a benefit has not been demonstrated specifically among transplant recipients with C3 glomerulonephritis (C3GN). The dose is targeted to a decrease in protein excretion to <1 gram/day. We generally give an ACE inhibitor or ARB even if the patient does not have hypertension. Among such patients, the dose may be limited by hypotension. For hypertensive patients, we also target a blood pressure <130/80 mmHg. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of renin-angiotensin system inhibitors on progression of CKD'.)
As for most transplant recipients, we also treat with a statin, primarily for cardiovascular benefit. (See "Lipid abnormalities after kidney transplantation", section on 'Treatment'.)
In such patients, we typically do not change the antirejection immunosuppressive regimen.
●Moderate disease – If proteinuria is ≥1.5 g/day but <3.5 g/day and eGFR is stable or declining slowly, we treat with ACE inhibitors or ARBs as described above for patients with mild disease. In addition, the patient’s baseline maintenance immunosuppression may be modified to increase the dose of antimetabolite (eg, mycophenolate) and/or prednisone. These drugs work by decreasing the inflammatory mediators that are recruited by anaphylatoxins during complement activation, but they do not directly affect the dysregulation of the complement pathway.
Complement inhibition with eculizumab, a monoclonal antibody against complement C5, can be used on a case-by-case basis, especially in patients with evidence of terminal complement pathway activation (ie, high sC5b-9 levels). Eculizumab has been reported to mitigate disease in a subset of patients with recurrent C3 glomerulopathy after transplantation, particularly those with rapidly progressive disease (with or without high sC5b-9 levels) [18-20]. Administration of eculizumab is similar to that for patients with C3 glomerulopathy of the native kidneys. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Eculizumab for refractory disease'.)
●Severe disease – Among patients who have proteinuria ≥3.5 g/day or rapidly declining eGFR, we give mycophenolate (1500 mg orally twice daily) with glucocorticoids (intravenous methylprednisolone 500 mg daily for three days followed by oral prednisone, 1 mg/kg/day with a maximum dose of 60 mg per day), until remission or for a maximum of 12 weeks. Patients who are taking azathioprine to prevent rejection should hold this agent while taking mycophenolate. As mentioned above, mycophenolate and glucocorticoids are not targeted therapies for recurrent C3 glomerulopathy. Their use, which is extrapolated from their use in other glomerular diseases, is thought to help reduce the inflammation associated with complement activation in this disorder.
Other therapies, such as eculizumab, rituximab, or plasma exchange, can be used on a case-by-case basis in patients with severe recurrent C3 glomerulopathy, particularly in those with autoantibodies or complement gene variants; however, data supporting the use of these agents in this setting are limited. Kidney transplant patients with clinical recurrence of C3 glomerulopathy should be enrolled in clinical trials (if available) for the newer anti-complement therapies.
Investigational therapies — A number of anti-complement therapies have been evaluated in patients with recurrent C3 glomerulopathy but are not yet approved for clinical use.
●Iptacopan – Iptacopan is an oral complement inhibitor that binds to complement factor B. In a phase II, open-label, single-arm trial that included 11 adult kidney transplant recipients with recurrent C3 glomerulopathy, treatment with iptacopan twice daily for 84 days decreased the median C3 deposit score on kidney allograft biopsy from 3.0 at baseline to 0.5 on day 84 [21]. Serum C3 levels normalized in most patients, and biomarkers of complement hyperactivity were reduced. Another study reported two "real-world" cases of recurrent C3 glomerulopathy who were treated with compassionate use of iptacopan and had a positive clinical response [22].
●Pegcetacoplan – Pegcetacoplan is a complement C3 inhibitor. In a phase II, open-label trial in which 10 patients with recurrent C3 glomerulopathy (n = 8) or recurrent immune complex membranoproliferative glomerulonephritis (n = 2) were treated with subcutaneous pegcetacoplan, the following results were reported at 12 weeks [23]:
•Eight (80 percent) patients showed a reduction in C3c staining (reflective of damage-causing deposits) by one or more orders of magnitude of intensity from baseline.
•Five (50 percent) patients showed a reduction in C3c staining by two or more orders of magnitude of intensity from baseline.
•Four (40 percent) patients showed zero staining intensity, indicating that C3c deposits were cleared.
In addition, a subgroup of patients with high baseline levels of proteinuria (≥1 g/day) experienced a 39 percent reduction of proteinuria from baseline. Other biomarkers also improved, including an increase in mean serum C3 levels, a reduction in mean sC5b-9 levels, and stabilization of kidney function as measured by estimated glomerular filtration rate (eGFR). There were no discontinuations due to treatment-emergent adverse events.
PROGNOSIS —
Recurrence often results in graft loss among patients with either dense deposit disease (DDD) or C3 glomerulonephritis (C3GN) [13,15,17,24].
●In one analysis that included 70 patients with C3 glomerulopathy (21 with DDD and 59 with C3GN), 20 progressed to end-stage kidney disease (ESKD) [24]. Of these, among six patients with DDD who underwent transplantation, disease recurred in all six patients and contributed to allograft loss in three patients. Among seven patients with C3GN who underwent transplantation, disease recurred in four and contributed to allograft loss in three. Allograft survival was estimated to be 94 percent at 1 year (95% CI 65-99), 69 percent at 5 years (95% CI 41-86), and 28 percent at 10 years (95% CI 6-56). Univariable analysis showed that kidney function impairment at the time of the first kidney biopsy, crescentic glomerulonephritis, and severe arteriolar sclerosis by light microscopy were predictive of ESKD.
●In another retrospective analysis of 34 patients with C3 glomerulopathy (3 with DDD, 26 with C3GN, 5 without classification) who underwent kidney transplantation, disease recurred in 21 patients (62 percent), including 14 (42 percent) of those with C3GN and all of those with DDD (100 percent) [15]. Among those with recurrent disease, 12 (57 percent) developed graft loss.
A histopathologic index has been developed to score kidney biopsy disease activity and chronicity in patients with C3 glomerulopathy [25]. In a retrospective study of 111 nontransplant patients with C3 glomerulopathy (87 with C3GN and 24 with DDD), total activity and total chronicity scores determined using this index were independent predictors of progression to advanced-stage chronic kidney disease and ESKD. Additional studies are needed to validate this histopathologic index among kidney transplant recipients with recurrent C3 glomerulopathy.
DE NOVO DISEASE —
Little is known about de novo C3 glomerulopathy in transplant recipients [26]. We believe such patients should be fully evaluated, as one would for patients with C3 glomerulopathy in the native kidney (see "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Establishing the diagnosis'). The treatment approach to de novo C3 glomerulopathy is the same as for recurrent disease. (See 'Treatment' above.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)
SUMMARY AND RECOMMENDATIONS
●Overview – Membranoproliferative glomerulonephritis (MPGN) may result from multiple causes including infection, autoimmune diseases, monoclonal gammopathies, and complement dysregulation. MPGN resulting from complement dysregulation is called C3 glomerulopathy. C3 glomerulopathy includes two subtypes: dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). (See 'Introduction' above and 'Classification and pathogenesis' above.)
●Epidemiology – The reported rate of recurrence of C3GN after transplantation is over 50 percent. The recurrence rate for patients with DDD is approximately 80 to 100 percent. (See "Membranoproliferative glomerulonephritis: Recurrence of idiopathic disease after transplantation" and 'Epidemiology and risk factors' above.)
●Clinical presentation – Patients usually present with signs of recurrence within one to two years following transplantation. Patients present with proteinuria, hematuria, increased creatinine, and/or hypocomplementemia. (See 'Clinical presentation' above.)
●Diagnosis evaluation – The diagnosis of recurrent complement-mediated MPGN is strongly suspected when patients with known DDD or C3GN in the native kidney present with proteinuria, hematuria, or a decline in estimated glomerular filtration rate (eGFR). The diagnosis is made by kidney biopsy. (See 'Diagnosis and evaluation' above.)
●Treatment – At this time, there is no universally effective treatment for recurrent complement-mediated MPGN. We suggest the following approach for patients with complement-mediated MPGN (including both DDD and C3GN) (see 'Approach to therapy' above):
•Mild disease – For patients with proteinuria <1.5 g/day and a stable eGFR, we suggest treating with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) (Grade 2C). This recommendation is based upon observed benefit in nontransplant recipients with proteinuric kidney disease. We target a protein excretion <1 gram/day and blood pressure <130/80 mmHg.
As for most transplant recipients, we also treat with a statin, primarily for cardiovascular benefit.
In such patients, we do not change the antirejection immunosuppressive regimen.
•Moderate disease – If proteinuria is ≥1.5 g/day but <3.5 g/day and eGFR is stable or declining slowly, we treat with ACE inhibitors or ARBs as described above for patients with mild disease. In addition, the patient’s baseline maintenance immunosuppression may be modified to increase the dose of antimetabolite (eg, mycophenolate) and/or prednisone. Complement inhibition with eculizumab can be used on a case-by-case basis, especially patients with evidence of terminal complement pathway activation (ie, high sC5b-9 levels). (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Moderate to severe disease'.)
•Severe disease – For patients with proteinuria ≥3.5 g/day and rapidly progressive disease (eg, crescentic glomerulonephritis), we suggest mycophenolate in combination with glucocorticoids (Grade 2C). Oral mycophenolate (1500 mg twice daily) may be given with pulse intravenous methylprednisolone (500 mg daily for three days), followed by mycophenolate at the same dose with oral prednisone (1 mg/kg/day with a maximum dose of 60 mg per day). This regimen may be continued until remission or for a maximum of 12 weeks. Patients who are receiving azathioprine for antirejection therapy should stop this while on mycophenolate.
Other therapies, such as eculizumab, rituximab, or plasma exchange, can be used on a case-by-case basis; however, data supporting the use of these agents in this setting are limited. Kidney transplant patients with clinical recurrence of C3 glomerulopathy should be enrolled in clinical trials (if available) for the newer anti-complement therapies.
