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. In addition, an MPGN pattern of injury may occur in the absence of an obvious cause. This is referred to as idiopathic MPGN.
Patients with MPGN may progress to end-stage kidney disease (ESKD) and require kidney replacement therapy, including dialysis and/or transplantation. Among patients who undergo transplantation, idiopathic MPGN and MPGN resulting from complement dysregulation commonly recur. Patients with MPGN that is secondary to infection, autoimmune disorders, and monoclonal gammopathies are generally not eligible for transplantation, unless the underlying cause is addressed.
This topic reviews recurrent idiopathic MPGN in the transplanted kidney. The recurrence in the transplanted kidney of MPGN resulting from complement dysregulation is discussed elsewhere. (See "C3 glomerulopathies: Recurrence 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 — MPGN is classified into subtypes, including immune complex-mediated MPGN 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.
A previously used system, which was based upon ultrastructural features observed by electron microscopy (EM), classifies MPGN into subtypes I, II, and III. MPGN type I generally refers to immune complex-mediated MPGN, though not necessarily idiopathic MPGN. Most studies of recurrent MPGN in the transplanted kidney used the EM-based classification. In order to discuss these studies, where possible, we include the older classification system as well as the more current system.
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'.)
Briefly, immune complex-mediated MPGN results from chronic antigenemia and/or circulating immune complexes [1-3]. Immune complex-mediated MPGN can result from chronic infections and autoimmune diseases (eg, lupus, Sjögren's disease, and systemic sclerosis) [4-13]. An underlying cause can be found in the majority of cases [1-3]. Occasionally, a cause is not identified, resulting in the diagnosis of idiopathic MPGN. Idiopathic MPGN is a diagnosis of exclusion [14].
C3 glomerulopathy results from dysregulation and persistent activation of the alternative complement pathway [1,2,15,16].
EPIDEMIOLOGY AND RISK FACTORS — The overall reported rate of recurrent idiopathic MPGN is between 18 and 48 percent [17-28]. The reported incidence in children may be somewhat higher [29].
These reported rates may overestimate the true recurrence rate of MPGN. This is because the diagnosis of MPGN is made by kidney biopsy (see 'Diagnosis and evaluation' below), and some of the histologic changes observed in MPGN are similar to those seen in chronic transplant rejection (transplant glomerulopathy) [30]. As a result, some patients diagnosed as having recurrent MPGN may actually have transplant glomerulopathy. Nevertheless, findings on electron microscopy (EM) may help distinguish between these two disorders [31]. (See 'Diagnosis and evaluation' below and "Kidney transplantation in adults: Chronic allograft nephropathy".)
Recurrence may be higher among recipients of living-related-donor kidneys, compared with deceased-donor kidneys. In one study that reported on recurrence in 32 patients with idiopathic MPGN type I, the disease recurrence rate was 33 percent in 27 patients who received a deceased-donor kidney and occurred in three of five patients who received living-related-donor kidneys [25].
Few data exist concerning recurrent disease in a second allograft. In one study, four of five patients who received a second transplant after losing the initial allograft as a result of recurrent MPGN also had recurrence in the second allograft [25].
Persistence or recurrence of hypocomplementemia after transplantation appears to be associated with an increased risk of recurrent MPGN, although disease recurrence can occur in the absence of this finding [26,32,33].
CLINICAL PRESENTATION — Most patients with recurrent idiopathic MPGN present with proteinuria, hematuria, hypertension, and a progressive decline in estimated glomerular filtration rate (eGFR). The amount of proteinuria is variable but is usually over 1 gram per day. In one report of 15 patients with recurrent MPGN, all patients presented with urine protein excretion of greater than 1 g/day [25].
Hypocomplementemia is commonly observed in patients with MPGN and may precede the kidney manifestations of recurrence [26,32].
DIAGNOSIS AND EVALUATION — The diagnosis of recurrent idiopathic MPGN is strongly suspected in a patient with a history of MPGN as the primary cause of end-stage kidney disease (ESKD) and who presents at any time after transplantation with new-onset proteinuria combined with various combinations of hematuria, hypertension, and a decline in estimated glomerular filtration rate (eGFR). The diagnosis is made by kidney allograft biopsy. A biopsy with analysis of tissue by light microscopy, immunofluorescence, and electron microscopy (EM) should be performed in all transplant recipients with suspected recurrent disease. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Pathology and pathogenesis'.)
The differential diagnosis includes all other causes of proteinuria, hematuria, and declining eGFR in the transplanted kidney.
The clinical utility of surveillance biopsies in patients with MPGN is uncertain. Although they may help diagnose recurrences earlier, they may lead to overtreatment of subclinical recurrences, especially since not all recurrences are clinically relevant or necessarily lead to graft loss. However, they may be a valuable tool in trials of novel complement inhibitors in the treatment of recurrent MPGN [33].
Transplant glomerulopathy may be difficult to distinguish from recurrent MPGN since some of the histologic features are similar [30]. However, findings on EM may help distinguish transplant glomerulopathy from MPGN [31]. Electron dense deposits are generally seen in MPGN but not in transplant glomerulopathy. Interstitial fibrosis and tubular atrophy and tubular basement membrane layering are seen with transplant glomerulopathy but not MPGN. C4d-positive staining of the peritubular capillaries may be observed in chronic antibody-mediated rejection, and donor-specific antibodies (DSAs) are usually present in patients with transplant glomerulopathy. (See "Kidney transplantation in adults: Chronic allograft nephropathy".)
For patients who present with recurrent MPGN, we exclude causes of secondary MPGN, which could occur even among patients who had idiopathic MPGN in the native kidney:
●We check for hepatitis B and C, human immunodeficiency virus (HIV), and bacterial infections in order to exclude infection-related secondary MPGN.
●We screen for lupus with antinuclear antibody (ANA), double-stranded DNA, and complement proteins C3 and C4 (see "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults"). Other autoimmune disorders that have been associated with MPGN (eg, Sjögren's disease and systemic sclerosis) would generally be excluded by characteristic history or physical findings.
●We measure DSAs in order to exclude transplant glomerulopathy.
TREATMENT — The treatment of recurrent MPGN due to secondary causes is directed at the cause.
There is no proven treatment for recurrent idiopathic MPGN.
We treat patients based upon the severity of the presentation:
●Mild disease – If the estimated glomerular filtration rate (eGFR) is stable and proteinuria is <1.5 g/day, 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 MPGN. The dose is targeted to a decrease in protein excretion to <1 gram/day. We generally give an ACE inhibitor or an ARB, even if the patient does not have hypertension. Among such patients, the dose may be limited by hypotension or hyperkalemia. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of renin-angiotensin system inhibitors on progression of CKD'.)
In addition, we target a blood pressure <130/80 mmHg. 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, in addition to the nonimmunosuppressive measures defined above, we increase the immunosuppressive regimen that the patient is already on for rejection. We increase the prednisone dose to 1 mg/kg per day (maximum dose of 60 to 80 mg daily) for 16 weeks, followed by a taper over several weeks.
If patients do not respond to the increased glucocorticoid dose with a decline in protein excretion and stabilization of eGFR by 16 weeks, we increase the dose of the antimetabolite (either azathioprine or mycophenolate). If the patient is on azathioprine, we increase the dose, as tolerated, to a maximum of 2.5 mg/kg daily. If the patient is on mycophenolate, we increase the dose, as tolerated, to a maximum dose of 1500 mg twice daily.
For patients who do not respond to or do not tolerate the increased dose of azathioprine or mycophenolate, cyclophosphamide may be given at a dose of 100 to 150 mg per day. There are case reports describing successful treatment with cyclophosphamide [34]. We discontinue the antimetabolite while the patient is on cyclophosphamide to mitigate the risk of myelosuppression. Generally, we do not continue cyclophosphamide for longer than 16 weeks, because of the potential for long-term side effects (see "General toxicity of cyclophosphamide in rheumatic diseases"). Thus, regardless of whether the patient has responded or not with a decrease in proteinuria or stabilization of eGFR, we switch back to azathioprine or mycophenolate (at the initial dose used to prevent rejection) after a maximum of 16 weeks.
●Severe disease – Among patients who have proteinuria ≥3.5 g/day, rapidly declining eGFR, or histologic findings of crescentic disease in the setting of rapidly progressive disease, we treat with daily or alternate-day plasmapheresis with albumin replacement fluid and with intravenous cyclophosphamide (one dose of 500 to 1000 mg/m2) and pulse intravenous methylprednisolone (500 to 1000 mg daily for three days), followed by oral prednisone (1 mg/kg/day with maximum of 60 to 80 mg per day). The combination of cyclophosphamide and plasmapheresis has been described to successfully treat patients with severe recurrent disease [35].
Among all patients who are treated with cyclophosphamide, the antimetabolite for antirejection should be held.
There are no convincing data to support the use of other therapies. An early report that the combination of aspirin and dipyridamole may stabilize kidney function has not been reproduced; thus, we do not recommend this approach [23]. (See "Membranoproliferative glomerulonephritis: Treatment and prognosis", section on 'Idiopathic immune complex-mediated MPGN'.)
Kidney transplant patients with clinical recurrence of MPGN are also ideal candidates for prospective studies with the newly developed complement inhibitors. Protocol biopsies may be of value in such trials for detecting recurrence at an early (and potentially reversible) stage and for monitoring the pathological response to treatment.
PROGNOSIS — Once immune complex-mediated MPGN recurs, graft loss is common [25,27,28,36]. In a retrospective analysis of 186 patients with immune complex-mediated MPGN (132 with idiopathic MPGN) who underwent kidney transplantation, disease recurred in 33 patients (18 percent), including 20 (15 percent) of those with idiopathic MPGN [28]. Among those with recurrent disease due to idiopathic MPGN, 13 (65 percent) developed graft loss. Seven of these 13 patients underwent a second kidney transplant; four (57 percent) subsequently had recurrent disease, and two developed graft loss.
DE NOVO MPGN AFTER TRANSPLANTATION — Occasionally, patients with a different primary disease (ie, involving the native kidney) will develop de novo immune complex-mediated MPGN in the allograft [37]. This is usually secondary to an underlying disease such as hepatitis C virus (HCV) infection [37]. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Immune complex/monoclonal immunoglobulin-mediated MPGN'.)
For transplant patients who present with de novo MPGN, in addition to excluding hepatitis B and C, human immunodeficiency virus (HIV), and bacterial infection, we obtain fungal cultures, exclude parasitic infection, and obtain abdominal/pelvic computed tomography (CT) scan to exclude abscesses. We exclude endocarditis with echocardiography and blood cultures.
As we do for patients with recurrent idiopathic MPGN, we screen for autoimmune disorders, particularly lupus, with antinuclear antibody (ANA), double-stranded DNA, and complement proteins C3 and C4. We check for monoclonal gammopathies with serum protein electrophoresis or serum free light chains and urine electrophoresis.
The treatment of de novo idiopathic MPGN is the same as for recurrent MPGN. (See 'Treatment' above.)
The treatment of secondary MPGN is a directed at the underlying cause:
●(See "Overview of kidney disease associated with hepatitis C virus infection".)
●(See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)
●(See "Hepatitis C virus infection in kidney donors".)
●(See "Hepatitis C infection in kidney transplant candidates and recipients".)
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) is a disease defined by a pattern of glomerular injury observed by light microscopy on kidney biopsy. MPGN is classified into subtypes, including immune complex-mediated and C3 glomerulopathy. Immune complex-mediated MPGN may result from infections and autoimmune diseases. Immune complex-mediated MPGN that occurs without a known cause is called idiopathic MPGN. C3 glomerulopathy results from complement dysregulation. Idiopathic MPGN and C3 glomerulopathy recur after kidney transplantation. (See 'Introduction' above and 'Classification and pathogenesis' above.)
●Epidemiology and risk factors – The reported rate of recurrent disease in idiopathic MPGN ranges between 20 and 48 percent. The incidence in children may be somewhat higher. Recurrence may be higher among living-related-donor kidneys. (See 'Epidemiology and risk factors' above.)
●Clinical presentation – The majority of patients with recurrent MPGN present with proteinuria, hematuria, a declining estimated glomerular filtration rate (eGFR), and hypertension. Patients may have hypocomplementemia. (See 'Clinical presentation' above.)
●Diagnosis – The diagnosis of recurrent idiopathic MPGN is strongly suspected in a patient who has a history of MPGN in the native kidney and presents at any time after transplantation with new-onset proteinuria, hematuria, and/or a decline in eGFR. The diagnosis is made by kidney biopsy. (See 'Diagnosis and evaluation' above.)
●Treatment – There is no proven treatment for recurrent idiopathic MPGN. (See 'Treatment' above.)
Our approach to treatment is based upon the severity of presentation:
•Mild disease – For patients with a stable eGFR and proteinuria that is <1.5 g/day, we suggest treating with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) (Grade 2C). This is based upon observed benefit in nontransplant recipients with proteinuric kidney disease. We target a blood pressure <130/80 mmHg. As for most transplant recipients, we also treat with a statin, primarily for cardiovascular benefit. (See 'Treatment' above.)
In such patients, we do not change the antirejection immunosuppressive regimen.
•Moderate disease – For patients with proteinuria ≥1.5 g/day but <3.5 g/day and eGFR that is stable or declining slowly, we suggest increasing the prednisone dose (Grade 2C). We generally increase the prednisone dose to 1 mg/kg per day (maximum dose of 60 to 80 mg daily) for 16 weeks, followed by a taper to the previous antirejection dose (ie, typically 5 mg daily) over several weeks.
For patients who do not respond to the increased glucocorticoid dose with a decline in protein excretion and stabilization of GFR, we suggest increasing the dose of the antimetabolite (Grade 2C). If the patient is on azathioprine, we increase the dose, as tolerated, to a maximum of 2.5 mg/kg. If the patient is on mycophenolate, we increase, as tolerated, to a maximum dose of 1500 mg twice daily. (See 'Treatment' above.)
•Severe disease – For patients who have proteinuria ≥3.5 g/day, rapidly declining eGFR, or histologic findings of crescentic disease in the setting of rapidly progressive disease, we suggest plasmapheresis with intravenous cyclophosphamide and pulse intravenous steroids (Grade 2C). We provide daily or alternate-day plasmapheresis with albumin replacement fluid. Intravenous cyclophosphamide may be given as a single dose of 500 to 1000 mg/m2, with pulse intravenous methylprednisolone (500 to 1000 mg daily for three days), followed by oral prednisone (1 mg/kg/day with maximum of 60 to 80 mg per day). For patients who are treated with cyclophosphamide, the antimetabolite for antirejection should be held. (See 'Treatment' above and "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis", section on 'Treatment'.)
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