Version May 2024
INTRODUCTION — Membranoproliferative glomerulonephritis (MPGN; also called mesangiocapillary or lobular glomerulonephritis) is a disease defined by a pattern of glomerular injury observed by light microscopy on kidney biopsy.
An MPGN pattern of injury may result from multiple causes including infection, autoimmune diseases, monoclonal gammopathies, and complement dysregulation. MPGN resulting from complement dysregulation is called C3 glomerulopathy.
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 — Membranoproliferative glomerulonephritis (MPGN) is classified into subtypes, including immune complex-mediated and C3 glomerulopathy. Immune complex-mediated MPGN is characterized by both immunoglobulin and complement protein deposition in the kidney, as identified by immunofluorescence microscopy. C3 glomerulopathy is characterized by predominant or exclusive C3 deposition.
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. Overactivation of the complement pathway can also be secondary to abnormal generation of a C3 convertase-stabilizing autoantibody called C3 nephritic factor (C3NeF) or to production of an autoantibody to factor H. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Pathogenesis'.)
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 [5-13]. The recurrence rate of dense deposit disease (DDD) is much higher and approaches approximately 80 to 100 percent [12-14]. Recurrence after transplantation occurs earlier and is more aggressive if associated with monoclonal gammopathy [13,14]. Other factors associated with an increased risk of recurrence include low complement levels, high levels of circulating autoantibodies (C3 nephritic factor and factor H autoantibody), rapid progression to end-stage kidney disease (ESKD) in the native kidneys, and living-related kidney transplantation [15].
CLINICAL PRESENTATION — Patients with recurrent C3 glomerulopathy typically present within one to two years following transplantation [12,13]. 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 [12,13]. 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 [13]. 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 is often performed in patients after a histologic diagnosis of C3 glomerulopathy is obtained since the identification of an abnormality in the alternative complement pathway informs immunosuppressive therapy. 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 [16].
We treat patients 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 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. In addition, we add treatment based upon the specific, underlying defect that causes complement dysregulation, if known. Eculizumab has been reported to mitigate disease in only a small number of patients with recurrent C3 glomerulopathy after transplantation [17-19]. Our treatment approach for specific complement abnormalities in patients with recurrent C3 glomerulopathies is similar to that for disease in the native kidney. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Plasma infusion or exchange for factor H defects' and "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Monoclonal gammopathy present'.)
The antirejection immunosuppressive regimen is generally continued unchanged among patients receiving plasma exchange or fresh frozen plasma (FFP) infusions, rituximab, or eculizumab.
●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.
Some clinicians also treat such patients with daily or alternate-day plasmapheresis with albumin replacement in addition to immunosuppressive therapy.
Patients with moderate or severe disease who have an identified serum factor deficiency and who achieve remission with the treatments may be treated with periodic FFP infusion.
Other therapies, such as eculizumab, rituximab, or plasma exchange, can be used on a case-by-case basis in patients with recurrent C3 glomerulopathy, particularly in those with autoantibodies or complement gene variants; however, data supporting the use of these agents in this setting are very limited. Kidney transplant patients with clinical recurrence of C3 glomerulopathy are ideal candidates for prospective studies with newly developed complement modulators.
PROGNOSIS — Recurrence often results in graft loss among patients with either dense deposit disease (DDD) or C3 glomerulonephritis (C3GN) [12,14,16,20].
●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) [20]. 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) [14]. 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 [21]. 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 [22]. 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 'Treatment' 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 as above, as well as providing specific treatment based upon the underlying etiology (ie, source of complement dysregulation), if known. This approach is similar to that in the native kidney and is described separately. (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. (See 'Treatment' above.)
Some experts also treat such patients with plasma exchange in addition to immunosuppressive therapy. In patients with a genetic cause of complement factor deficiency, we would treat with periodic fresh frozen plasma (FFP) infusion after remission is achieved. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Rapidly progressive glomerulonephritis'.)
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