Version May 2024
INTRODUCTION — Membranoproliferative glomerulonephritis (MPGN) is a pattern of glomerular injury on kidney biopsy with characteristic light microscopic changes, including hypercellularity and thickening of the glomerular basement membrane (GBM). MPGN is a histologic lesion and not a specific disease entity. As such, the discovery of the lesion of MPGN in a kidney biopsy is the start of an exploratory process leading to a diagnosis, not an end in itself.
This topic will review the pathology, pathogenesis, classification, clinical features, and diagnosis of MPGN. The treatments of the different types of MPGN, including recurrent MPGN following kidney transplantation, are discussed elsewhere:
●(See "Membranoproliferative glomerulonephritis: Treatment and prognosis".)
●(See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis".)
●(See "Membranoproliferative glomerulonephritis: Recurrence of idiopathic disease after transplantation".)
PATHOLOGY AND PATHOGENESIS — MPGN, also known as mesangiocapillary glomerulonephritis, is a pattern of glomerular injury on light microscopy that is characterized by mesangial hypercellularity, endocapillary proliferation, and double-contour formation along the glomerular capillary walls (picture 1A-B). The term "MPGN" is derived from the two characteristic histologic changes:
●Thickened glomerular basement membrane (GBM) due to deposition of immune complexes and/or complement factors, interposition of the mesangial cell and other cellular elements between the GBM and the endothelial cell, and new basement membrane formation.
●Increased mesangial and endocapillary cellularity, often leading to a lobular appearance of the glomerular tuft. The increase in cellularity results from both proliferation of mesangial cells and influx of circulating monocytes.
Two primary mechanisms have been described in the pathogenesis of MPGN:
●Deposition of immune complexes or monoclonal immunoglobulins leading to activation of complement (immune complex/monoclonal immunoglobulin mediated). The immune complexes can be composed of environmental or autologous antigens, and some instances represent aggregation of monoclonal proteins, typically of the immunoglobulin family. The term "immune complex-mediated MPGN" is best applied in the infectious setting since a specific antigen is not documented in cases of MPGN associated with autoimmunity or a monoclonal gammopathy. (See 'Immune complex/monoclonal immunoglobulin-mediated MPGN' below.)
●Dysregulation and persistent activation of the alternative complement pathway (complement mediated). (See 'Complement-mediated MPGN' below.)
CLASSIFICATION BASED UPON IMMUNOFLUORESCENCE MICROSCOPY — MPGN has traditionally been classified as MPGN types I, II, and III based upon electron microscopic findings. However, advances in the understanding of processes involved in the pathogenesis of MPGN suggest that the electron microscopy (EM)-based classification can result in overlap among the types (algorithm 1) [1]. (See 'Classification based upon electron microscopy' below.)
By contrast, a classification that is based upon the pathogenetic process helps to direct the clinical evaluation and provide a rationale for disease-specific treatments. In this system, MPGN is classified as being mediated by immune complexes or monoclonal immunoglobulins, complement dysregulation that leads to persistent activation of the alternative complement pathway, or, rarely, mechanisms not involving immunoglobulin or complement deposition, such as endothelial injury [2]. These disorders can be distinguished by immunofluorescence microscopy [3,4].
Immune complex/monoclonal immunoglobulin-mediated MPGN is characterized by the deposition of immunoglobulins and complement components, while complement-mediated MPGN is characterized by glomerular deposits of complement components in the absence of significant immunoglobulin deposition.
Immune complex/monoclonal immunoglobulin-mediated MPGN — Immune complex-mediated MPGN results from chronic antigenemia and/or circulating immune complexes and can be seen in chronic infections and autoimmune diseases [5,6]. MPGN with immunoglobulin and complement deposits may also be observed in the setting of monoclonal gammopathies [7-16]. An underlying cause can be found in the great majority of cases [3,4,17], but despite a thorough evaluation, a small minority remain "idiopathic."
Immunofluorescence microscopy may suggest the underlying etiology of immune complex/monoclonal immunoglobulin-mediated MPGN:
●MPGN resulting from hepatitis C virus (HCV) infection typically shows granular deposition of immunoglobulin M (IgM), C3, and both kappa and lambda light chains. Immunoglobulin G (IgG) may or may not be present, and C1q is typically negative [18]. This pattern may also be seen with MPGN induced by other viral infections [18].
●MPGN resulting from monoclonal gammopathy is characterized by deposition of monotypic immunoglobulin with kappa or lambda light chain restriction but not both. MPGN associated with either heavy or light chain deposition alone has also been described [12,19]. (See 'Monoclonal gammopathies' below.)
●MPGN resulting from autoimmune diseases is typically characterized by the "full house" pattern of immunoglobulin deposition, including IgG, IgM, immunoglobulin A (IgA), C1q, C3, C4, and kappa and lambda light chains [20].
EM in immunoglobulin-positive MPGN typically demonstrates subendothelial and mesangial deposits (picture 2). Subepithelial deposits can also be seen with autoimmune diseases. As an example, patients with diffuse proliferative lupus nephritis can also have lupus membranous glomerulopathy with subepithelial deposits (picture 3) [18]. However, EM alone does not differentiate between immune complex/monoclonal immunoglobulin-mediated and complement-mediated MPGN.
EM may suggest certain underlying diseases. As examples, tubuloreticular structures in endothelial cells in MPGN are suggestive of lupus nephritis (picture 4), and a fingerprint pattern associated with cryoprecipitates is seen in mixed cryoglobulinemia (picture 5) or rarely in lupus nephritis associated with cryoglobulinemia [21]. Intramembranous, linear, highly electron-dense deposits, with sausage-shaped deposits, are suggestive of dense deposit disease (DDD).
Infections — Immune complex-mediated MPGN is most commonly secondary to hepatitis C and B viral infections [11,18,22-24]. The incidence of HCV-associated MPGN varies with location. As examples, HCV appears to be a common cause of MPGN in Japan [9] but is an uncommon cause in France and South Africa [25,26]. HCV-induced MPGN is typically associated with mixed (type II) cryoglobulinemia.
In addition to HCV, chronic bacterial (eg, endocarditis, shunt nephritis, abscesses), fungal, and, particularly in the developing world, parasitic infections (eg, schistosomiasis, echinococcosis) can cause MPGN [9,10,27-29].
●(See "Schistosomiasis and glomerular disease", section on 'Clinicopathologic manifestations'.)
Autoimmune disorders — Immune complex-mediated MPGN is observed in patients with systemic lupus erythematosus (particularly in the chronic phase of lupus nephritis) and, less often, Sjögren's disease or rheumatoid arthritis [15,16,30,31].
●(See "Lupus nephritis: Diagnosis and classification", section on 'Diffuse LN (class IV)'.)
●(See "Kidney disease in primary Sjögren's disease", section on 'Nephritic syndrome'.)
Monoclonal gammopathies — Monoclonal gammopathies are an important cause of MPGN and can be associated on immunofluorescence microscopy with either monoclonal immunoglobulin deposition, as discussed in this section [14,32-39], or isolated complement deposition in DDD and C3 glomerulonephritis (C3GN), as discussed below. (See 'Complement-mediated MPGN' below and 'C3 dense deposit disease' below.)
In a retrospective review of kidney biopsies performed at the Mayo Clinic, 28 of 68 patients (41 percent) who had a diagnosis of MPGN and were not infected with either hepatitis B or C virus had a monoclonal gammopathy, as determined by serum and/or urine electrophoresis [14]. A diagnosis of monoclonal gammopathy of undetermined significance (MGUS) was made in 16 patients; the 12 remaining patients had lymphoma or multiple myeloma. Most cases of MPGN and monoclonal immunoglobulin deposits (ie, proliferative glomerulonephritis with monoclonal immunoglobulin deposits [PGNMID]) are not associated with a symptomatic hematological disease but occur in the setting of a small, otherwise asymptomatic plasma cell or B cell clone. This situation in commonly referred to as monoclonal gammopathy of renal significance (MGRS) [40].
The clinical features and prognosis of PGNMID were described in a study of 37 patients who had monoclonal IgG deposits [37]. Nephrotic syndrome, kidney function impairment, and hematuria were present in 49, 68, and 77 percent, respectively. Of 32 patients who were followed for over two years, 22 percent progressed to end-stage kidney disease (ESKD), 38 percent had complete or partial recovery, and 38 percent had persistent kidney dysfunction. Only one patient had multiple myeloma.
For unclear reasons, most patients with PGNMID do not have a detectable circulating monoclonal gammopathy by serum and urine monoclonal protein testing and do not have detectable plasma cell or B cell clones on bone marrow aspirate and biopsy. There is a greater likelihood of finding a plasma cell clone by bone marrow biopsy if the monoclonal IgG is an IgG1 subtype or if the PGNMID is a light chain only variant [19]. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'Establishing the diagnosis'.)
Cases of MPGN in patients with chronic lymphocytic leukemia have also been described, usually in association with mixed cryoglobulinemia or noncryoprecipitating monoclonal IgG or IgM [39,41]. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Other organ involvement'.)
Patients with MPGN associated with monoclonal immunoglobulin deposits (PGNMID) have a very high rate of recurrent disease (approximately 70 percent) after kidney transplantation [42,43]. Recurrence typically occurs early posttransplant and is characterized by an aggressive course and high risk of graft failure [42,43]. Biopsy of the allograft often shows a mesangial proliferative pattern of injury that subsequently progresses to an MPGN pattern. Glomerular deposits are most often composed of IgG3 kappa, although other immunoglobulin isotypes and/or light chains have also been identified in the deposits; the prognostic implications of these immunoglobulin variations are unclear [42]. In two-thirds of cases (mainly IgG3 subtype), a monoclonal immunoglobulin cannot be detected in the serum or urine, and in these cases, bone marrow biopsy shows no evidence of a plasma cell disorder. In the other one-third of the patients, a monoclonal protein can be identified in the serum or urine, but most patients have an MGRS rather than multiple myeloma. (See "Membranoproliferative glomerulonephritis: Recurrence of idiopathic disease after transplantation".)
MPGN with masked deposits — In rare cases, patients with MPGN associated with monoclonal gammopathy may present with isolated C3 deposits with no staining of immunoglobulins by standard immunofluorescence techniques [44]. Immunofluorescence on formalin-fixed, paraffin-embedded tissue after pronase digestion may reveal the presence of "masked" monoclonal immunoglobulin deposits. Positive staining for C4d, a byproduct of the classic and lectin complement pathways, can also be helpful in detecting "masked" immune deposits [45,46]. The immunoglobulin detected within glomerular deposits typically matches the monoclonal protein identified by serum or urine immunofixation in these patients. Failure to identify these "masked" monoclonal immunoglobulins can result in missing the diagnosis of monoclonal gammopathy-associated MPGN and incorrectly diagnosing these patients as having only C3GN. It is important that these cases are not misdiagnosed as C3 glomerulopathy, as most are associated with a low-grade lymphoma or plasma cell dyscrasia. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'When to suspect MGRS'.)
Rare causes — Rare causes of MPGN include non-Hodgkin lymphoma [47], renal cell carcinoma [48], splenorenal shunt surgery for portal hypertension [49], melanoma [50], and alpha-1-antitrypsin deficiency [51]. Idiopathic MPGN is a diagnosis of exclusion [52] and is seldom encountered if the diagnostic evaluation is thorough. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Glomerulonephritis'.)
Complement-mediated MPGN — Complement-mediated MPGN is less common than immune complex/monoclonal immunoglobulin-mediated MPGN and results from dysregulation and persistent activation of the alternative complement pathway [3,4,29,30]. This form of MPGN is due to the deposition of complement products along the capillary walls and in the mesangium. Complement-mediated MPGN can be subdivided into C3 glomerulopathy and C4 glomerulopathy based upon the complement product identified within glomerular deposits. In C3 glomerulopathy, immunofluorescence microscopy of kidney sections demonstrates predominantly bright staining for C3, with minimal or no immunoglobulin staining, in the mesangium and along the capillary walls (picture 6) [53]. C4 glomerulopathy is characterized by bright staining for C4d, a degradation product of C4, with minimal or no C3 or immunoglobulin staining (picture 7).
Complement-mediated MPGN may be further classified based upon ultrastructural features observed on EM as DDD or C3 (or C4) glomerulonephritis. Some genetic mutations that have been associated with these disorders are also associated with atypical hemolytic uremic syndrome. (See "Complement-mediated hemolytic uremic syndrome in children".)
Hypocomplementemia is a characteristic finding in most patients with MPGN. However, a normal C3 concentration does not exclude complement-mediated MPGN, and it is not unusual to find a normal C3 concentration in the chronic phases of the disease, as in adults with DDD [54] or patients with C3GN [55]. Low C3 levels are also common in postinfectious glomerulonephritis and cannot be used to distinguish these two entities. However, anti-factor B antibodies have been reported to occur more frequently in children with acute postinfectious glomerulonephritis than in children with hypocomplementemic C3 glomerulopathy (91 versus 14 percent) [56]. (See 'Clinical features' below.)
C3 glomerulopathy
C3 dense deposit disease — C3 DDD (also called MPGN type II) is a rare form of MPGN that affects both children and young adults. It has also been associated with monoclonal gammopathies in older adults [57]. In the majority of patients, antibodies called C3 nephritic factors (C3NeFs) that stabilize C3 convertase are present in circulation. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis".)
On light microscopy, patterns of injury other than MPGN can also be seen, including mesangial proliferative, diffuse proliferative, crescentic glomerulonephritis, and a sclerosing glomerulopathy. Immunofluorescence microscopy demonstrates C3 deposits, and EM (required to establish the diagnosis) shows the characteristic sausage-shaped, wavy, densely osmophilic deposits along the glomerular basement membranes (GBM) and mesangium (from which the disease receives its name) (picture 8). C3 DDD may be associated with lipodystrophy and presence of drusen on funduscopic examination. Rarely C3 DDD can be a consequence of a monoclonal gammopathy that interferes with the interaction of complement factor H and C3b causing persistent activation of the alternate complement pathway. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Clinical features'.)
C3 glomerulonephritis — C3GN (also called glomerulonephritis with isolated C3 deposits) is, like C3 DDD, caused by excessive activation of the alternative complement cascade due (in most patients) to mutations in or antibodies to complement regulating proteins [3,55,58-62]. C3GN has also been reported in association with inherited disease due to mutations in the CFHR5 gene (CFHR5 nephropathy) and a mutation producing a CFHR1-CFHR3 hybrid gene as well as with monoclonal gammopathies [63,64]. In one study of 95 patients with C3GN, among those 50 years and older, more than 60 percent had a circulating monoclonal protein [65]. This is in contrast to younger patients who are more likely to have genetic variants and/or autoantibodies to complement regulating proteins and do not have circulating monoclonal proteins. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance" and 'CFHR5 nephropathy' below.)
Light microscopy often shows an MPGN pattern of injury, although other forms of glomerulonephritis may be seen, including mesangial proliferative, diffuse proliferative, crescentic glomerulonephritis, and a sclerosing glomerulopathy [58,59,66-68]. C3GN with severe crescentic glomerulonephritis is a rare subtype that more commonly affects children and young adults [69].
Immunofluorescence microscopy shows extensive C3 deposition along the capillary walls and mesangium (picture 6) with no significant immunoglobulin deposition [3,58,59,70]. EM demonstrates deposits that are similar to those seen with immune complex/monoclonal immunoglobulin-mediated MPGN but does not show the typical sausage-shaped intramembranous and mesangial deposits observed in DDD (picture 9).
Patients with C3GN typically present with proteinuria, which can be associated with nephrotic syndrome, hematuria, and variable degrees of hypertension and azotemia. C3 levels are low in less than 50 percent of cases, C4 levels are normal, and some patients have a C3 convertase-stabilizing autoantibody called C3 nephritic factor (or C3NeF), which is also seen in DDD [58-60]. A normal C3 does not exclude C3GN [55,71]. There may be progression to ESKD, and C3GN can recur after kidney transplantation.
Some patients develop hematuria after an upper respiratory infection (URI). In a report of nine patients who presented with hematuria following a nonstreptococcal URI and had glomerulonephritis on kidney biopsy, six had mesangial C3 deposits, and four had hypocomplementemia [72]. These findings suggest that the patients may have had a form of C3GN that had not been described at the time of publication. In addition, hematuria after a URI is well described in CFHR5 nephropathy, as described in the next section. The presence of drusen on funduscopic examination has also been reported in patients with C3GN [73].
CFHR5 nephropathy — A familial form of C3GN has been described in patients of Cypriot origin due to a mutation in the gene for complement factor H-related protein 5 (CFHR5) [74,75]. In a cohort of 84 Cypriots with unexplained kidney disease, four (5 percent) had CFHR5 nephropathy, as detected by mutation analysis [74].
CFHR5 nephropathy has the following genetic features [76]. Inheritance is autosomal dominant with more than 90 percent penetrance. The mutation involves a genomic duplication in the CFHR5 gene that results in an elongated version of the CFHR5 protein. The mutation is present in approximately 1 in 6500 Cypriots and is associated with an extended haplotype flanking the mutation, pointing toward a common ancestor.
The clinical manifestations include hematuria in approximately 90 percent, accompanied by proteinuria in 38 percent [75]. Episodes of macroscopic (gross) hematuria can occur within one to two days of a URI and can be recurrent [74]. The serum C3 concentrations at presentation have been poorly characterized among patients with CFHR5 nephropathy. Among CHFR5 mutation carriers over age 50 years, men are much more likely than women to develop chronic kidney disease (80 versus 21 percent) and ESKD (78 versus 4 percent) [75]. The development of proteinuria (greater than 1 to 1.5 g/day) is a major predictor of a progressive disease [75]. Recurrent nephropathy can occur in transplanted kidneys [77]. There is no treatment of proven efficacy.
Distinction from postinfectious glomerulonephritis — Some patients with MPGN have subepithelial and subendothelial deposits on EM (ie, MPGN type III as described below) and are complement positive but immunoglobulin negative by immunofluorescence microscopy. Some of these cases have been attributed to resolving postinfectious glomerulonephritis because of the presence of subepithelial deposits on EM, even in the absence of a history of recent infection. Atypical, persistent, or resolving postinfectious glomerulonephritis are terms that have been used to describe such cases. In such cases, bright C3 staining and lack of significant immunoglobulin staining raise the possibility of C3GN. Consistent with this hypothesis, abnormalities in the alternative complement pathway have been found in many of these patients [55,78-81] and likely represent cases of undiagnosed C3GN [81]. By contrast, postinfectious glomerulonephritis is associated with both bright C3 staining and IgG deposition (picture 10).
Findings on EM may also help to distinguish C3GN from postinfectious glomerulonephritis. C3GN is usually associated with abundant large mesangial, subendothelial, and occasionally subepithelial or intramembranous deposits that have a fuzzy amorphous lobular quality (picture 9). This is in contrast to the well-demarcated subepithelial humps seen in postinfectious glomerulonephritis (picture 11). (See "Poststreptococcal glomerulonephritis", section on 'Pathology'.)
Low C3 levels are common in both postinfectious glomerulonephritis and C3GN and cannot be used to distinguish these two entities. However, anti-factor B antibodies have been reported to occur more frequently in children with acute postinfectious glomerulonephritis than in children with hypocomplementemic C3 glomerulopathy (91 versus 14 percent) [56].
C4 glomerulopathy — C4 glomerulopathy, which includes C4 DDD and C4GN, is a rare disorder characterized by the glomerular deposition of C4 in the absence of C3, C1q, and immunoglobulin [82,83]. Unlike patients with C3 glomerulopathy, those with C4 glomerulopathy do not have congenital or acquired defects in the alternative pathway of complement; however, they may have an overactive lectin pathway of complement. A more detailed discussion of C4 glomerulopathy is presented separately. (See "C4 glomerulopathy".)
MPGN without immunoglobulin or complement deposition — A histologic pattern that may resemble MPGN on light microscopy can be seen in the healing phase of thrombotic microangiopathies (eg, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome), antiphospholipid antibody syndrome, nephropathy associated with bone marrow transplantation, chronic kidney allograft nephropathy, radiation nephritis, and malignant hypertension.
●(See "Diagnosis of immune TTP", section on 'Neurologic and other organ involvement'.)
The common underlying cause of the MPGN pattern in such patients is endothelial injury followed by reparative changes. Immunofluorescence microscopy does not show significant immunoglobulin or complement deposition in the glomeruli, and EM does not show electron-dense deposits along the capillary walls.
CLASSIFICATION BASED UPON ELECTRON MICROSCOPY — MPGN was initially classified into types I, II, and III based upon electron microscopy (EM). However, this classification has important limitations, and we prefer the classification based upon immunofluorescence microscopy. The classification based upon EM is presented here solely for historical reasons. (See 'Limitations of this classification' below.)
MPGN type I — MPGN type I is characterized by discrete immune deposits in the mesangium and subendothelial space, similar to that seen in lupus nephritis, that are thought to reflect the deposition of circulating immune complexes (picture 2).
MPGN type II — MPGN type II (dense deposit disease [DDD]) is characterized by continuous, dense ribbon-like deposits along the basement membranes of the glomeruli, tubules, and Bowman's capsule (picture 8) [84-86]. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis".)
MPGN type III — MPGN type III is similar to MPGN type I except that subepithelial deposits are noted as well as subendothelial deposits (picture 12). Based upon the EM findings, MPGN type III is further classified into two principal variants, the Strife and Anders variant and the Burkholder variant, which have different patterns of electron-dense deposits and disorganization of the glomerular basement membrane (GBM) [87-90].
Many cases of MPGN type III that are immunoglobulin negative but complement positive by immunofluorescence microscopy have been attributed to resolving postinfectious glomerulonephritis because of the presence of subepithelial humps on EM, despite the absence of a history of recent infection. In such cases, bright C3 staining and lack of significant immunoglobulin staining raise the possibility of C3 glomerulonephritis (C3GN). Consistent with this hypothesis, subsequent evaluation demonstrated abnormalities of the alternative complement pathway in many of these patients. (See 'C3 glomerulonephritis' above.)
Limitations of this classification — Understanding the limitations of the EM classification requires a brief review of complement activation pathways. There are two main pathways: the classic pathway, which is activated when IgG or IgM antibodies bind to antigens, and the alternative pathway, which does not require the presence of antibodies and can be autoactivated by spontaneous cleavage of C3 to C3b, leading to the formation of C3 convertase (figure 1). (See "Overview and clinical assessment of the complement system", section on 'Pathways and activating conditions'.)
The EM-based classification can result in overlap between types I and III. Both types have been considered to be immune complex-mediated glomerulonephritides because of the presence of immune-type electron-dense deposits in the mesangium and subendothelial space. However, the following observations suggest that some cases with EM features of MPGN type I or MPGN type III are mediated by complement, not immune, complexes:
●Some cases of MPGN type I have been associated with strong C3 staining without immunoglobulin staining by immunofluorescence microscopy, consistent with a process mediated by complement alternative pathway rather than immune complexes [91]. (See 'Complement-mediated MPGN' above.)
●The majority of cases of MPGN type III show strong C3 staining without immunoglobulin staining by immunofluorescence microscopy, again consistent with a process mediated by complement alternative pathway rather than immune complexes.
●Markedly depressed serum C3 levels with normal or only mildly decreased serum C4 and C1q levels have been observed in patients with MPGN type I, suggesting possible activation of the alternative rather than the classical complement pathway activated by immune complexes [88].
●A C3 convertase-stabilizing antibody (called C3 nephritic factor [C3NeF]) is found in approximately 80 percent of patients with DDD and results in activation of the alternative complement pathway that characterizes DDD. However, different C3NeFs have been identified in some patients with MPGN types I and III [92,93]. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Pathogenesis'.)
●There is an inherited form of MPGN type III that is linked to chromosome 1q32, the locus for the complement receptor family [94,95]. These genes code for a highly homologous group of proteins that regulate C3 convertase activity. Abnormalities in any of these proteins may cause excess circulating C3b, mimicking the action of C3NeF [94]. (See "Regulators and receptors of the complement system".)
CLINICAL FEATURES — The clinical presentation of MPGN is similar to that in other types of glomerulonephritis. In patients with active disease, the urine sediment reveals hematuria, typically with dysmorphic red cells (picture 13 and picture 14) and occasionally with red cell casts (picture 15); there is a variable degree of proteinuria; and the serum creatinine may be normal or elevated. Occasional patients with indolent disease present late in the course at a time when active inflammation has subsided. Such patients may have a bland urine sediment with a variable degree of proteinuria and elevation in serum creatinine. The diagnosis is made by kidney biopsy [1]. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)
Hypocomplementemia is common in all types of MPGN [18,54,85,87,96]. In immune complex/monoclonal immunoglobulin-mediated MPGN, complement activation occurs via the classic pathway and is typically manifested by a normal or mildly decreased serum C3 concentration and a low serum C4 concentration. In complement-mediated MPGN, there are usually low serum C3 and normal C4 levels due to activation of the alternate pathway [85]. However, complement-mediated MPGN is not excluded by a normal serum C3 concentration, and it is not unusual to find a normal C3 concentration in adults with dense deposit disease (DDD) [54] or C3 glomerulonephritis (C3GN). (See 'Complement-mediated MPGN' above.)
Among patients who have the different forms of MPGN described above, there are generally no differences in clinical presentation with the possible exception of patients with DDD, which is a form of complement-mediated MPGN that is associated with drusen formation that may be seen on funduscopic examination and with partial lipodystrophy. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Clinical features'.)
EVALUATION OF THE PATIENT WITH AN MPGN LESION — As previously stated, MPGN is a histologic lesion and not a specific disease entity. The identification of an MPGN lesion in a kidney biopsy does not establish a specific diagnosis; rather, it should prompt the clinician to pursue a thorough evaluation to determine the underlying cause of the MPGN lesion. (See 'Classification based upon immunofluorescence microscopy' above.)
Classification of the MPGN lesion — The causes and evaluation of MPGN differ in immune complex/monoclonal immunoglobulin-mediated, complement-mediated disease, and MPGN without immunoglobulin and complement deposition. Thus, the initial step we take in evaluating the patient with an MPGN lesion is to classify the MPGN lesion based upon the immunofluorescence microscopy findings on kidney biopsy (algorithm 1) (see 'Classification based upon immunofluorescence microscopy' above):
●Patients with positive staining for polyclonal immunoglobulins and complement by immunofluorescence microscopy most likely have immune complex-mediated MPGN. (See 'Immune complex/monoclonal immunoglobulin-mediated MPGN' above.)
●Patients with MPGN with monoclonal immunoglobulin deposits most likely have an underlying clonal B cell or plasma cell disorder.
●Patients with positive staining for C3 (or, rarely, C4d) and no or minimal staining for immunoglobulin by immunofluorescence microscopy (picture 6) most likely have complement-mediated MPGN. (See 'Complement-mediated MPGN' above.)
●Patients with no or minimal staining for immunoglobulin and complement most likely have MPGN as a result of endothelial injury followed by reparative changes. (See 'MPGN without immunoglobulin or complement deposition' above.)
Subsequent evaluation based upon classification — Subsequent evaluation for the cause of the MPGN lesion is based upon the classification of the MPGN lesion:
●Immune complex/monoclonal immunoglobulin-mediated MPGN – In patients who have findings consistent with immune complex/monoclonal immunoglobulin-mediated MPGN, we evaluate for the following disorders:
•Infections – A variety of infections can lead to MPGN. Hepatitis B and hepatitis C virus (HCV) should be excluded by serology, while chronic bacterial infections should be excluded by culture, including blood cultures when clinically indicated. We do not test for fungi in the absence of a suggestive history (eg, fever of unknown origin, unexplained pulmonary infiltrates) or for parasitic infections (eg, malaria, schistosomiasis, leishmaniasis) unless the patient resides in or has visited an endemic site. Patients with a history of recent sore throat or skin infection should undergo serologic testing for recent streptococcal infection. Antibodies to factor B have been described as frequently occurring in patients with acute postinfectious glomerulonephritis in children [56]. (See "Hepatitis B virus: Screening and diagnosis in adults" and "Screening and diagnosis of chronic hepatitis C virus infection" and "Evaluation of acute pharyngitis in adults", section on 'Testing for GAS'.)
•Autoimmune diseases – Autoimmune diseases that have been associated with MPGN include systemic lupus erythematosus and rarely Sjögren's disease and systemic sclerosis [15,30,31,97]. Such patients almost always have manifestations of the underlying disease, and other than serologic testing for lupus, we would not evaluate for Sjögren's disease and systemic sclerosis in the absence of suggestive manifestations. The specific evaluation of these disorders is discussed elsewhere. (See "Lupus nephritis: Diagnosis and classification", section on 'Evaluation and diagnosis' and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Diagnosis and classification of Sjögren’s disease" and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)
•Monoclonal gammopathy – Monoclonal gammopathies should be excluded by serum protein electrophoresis and immunofixation, serum free light chains, and urine protein electrophoresis and immunofixation. Newer techniques for detecting plasma cell disorders based on mass spectrometry are emerging, which have improved clinical and analytical performance when compared with immunofixation [98,99].
Urine free light chains have no diagnostic utility and should not be performed. Bone marrow examination may be required to identify the clone (B cell or plasma cell) producing the pathogenic monoclonal immunoglobulin, in order to delivery appropriate chemotherapy. However, the yield of a bone marrow biopsy finding a clone in the absence of a circulating monoclonal protein is low. Most patients with MPGN and a monoclonal gammopathy have no identifiable disease; this disorder has been called MPGN associated with monoclonal gammopathy of renal significance (MGRS) [100]. In a report from the Mayo Clinic of 68 patients with MPGN who were not infected with HCV, 28 (41 percent) had a monoclonal gammopathy on serum and/or urine electrophoresis [14]. Most of these patients had no identifiable underlying disease and were considered to have monoclonal gammopathy of undetermined significance (MGUS). (See "Diagnosis of monoclonal gammopathy of undetermined significance".)
However, occasional patients with a monoclonal gammopathy and MPGN have a serious and potentially treatable cause. These include multiple myeloma, low-grade B cell lymphoma, and chronic lymphocytic leukemia [14,37,39,101]. These disorders may be diagnosed at presentation or later after an initial diagnosis of MGUS [101]. As described below, treatment of these disorders can lead to improvement in the MPGN. (See "Membranoproliferative glomerulonephritis: Treatment and prognosis", section on 'Patients with an underlying cause'.)
●Complement-mediated MPGN – In patients who have findings consistent with complement-mediated MPGN, we perform an evaluation for activation of the alternative pathway of complement [102,103]. We suggest measuring C3, C4, CH50 (which provides a measure of activation of the classic complement pathway), and AH50 (which provides a measure of activation of the alternative complement pathway). All patients with a complement-mediated MPGN should undergo genetic analysis for mutations and allele variants of complement factors and assays for autoantibodies to complement regulating proteins (eg, factors H and I), including testing for C3 nephritic factor (C3NeF) and, if available, serum levels of the membrane attack complex. Factor H and other measurements, including C3 activation and breakdown products, C3NeF, and mutation screening of a variety of complement related genes including factor H are available in select research laboratories (table 1). A plasma cell disorder should also be excluded [14,63,65,104]. (See 'Complement-mediated MPGN' above and "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Establishing the diagnosis'.)
●In patients who have findings consistent with MPGN without immunoglobulin or complement deposition, we evaluate for causes of chronic thrombotic microangiopathy (eg, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome) as well as for antiphospholipid antibody syndrome. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Diagnosis of antiphospholipid syndrome".)
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
●General principles – Membranoproliferative glomerulonephritis (MPGN) is a pattern of glomerular injury on kidney biopsy with characteristic light microscopic changes, including hypercellularity and thickening of the glomerular basement membrane (GBM). MPGN is a histologic lesion and not a specific disease entity. As such, the discovery of the lesion of MPGN in a kidney biopsy is the start of an exploratory process leading to a diagnosis, not an end in itself. (See 'Introduction' above.)
●Classification – MPGN has traditionally been classified as MPGN types I, II, and III based upon electron microscopic findings. However, electron microscopy (EM)-based classification can result in overlap among the types. As such, the EM classification for MPGN is primarily of historical interest, and its use should be discouraged. (See 'Classification based upon electron microscopy' above.)
By contrast, a classification that is based upon the pathogenetic process helps to direct the clinical evaluation and provide a rationale for disease-specific treatments. In this system, MPGN is classified as being mediated by immune complexes or monoclonal immunoglobulins, complement dysregulation that leads to persistent activation of the alternative complement pathway, or, rarely, mechanisms not involving immunoglobulin or complement deposition, such as endothelial injury. These disorders can be distinguished by immunofluorescence microscopy. (See 'Classification based upon immunofluorescence microscopy' above.)
●Clinical features – The clinical presentation of MPGN is similar to that in other types of glomerulonephritis. In patients with active disease, the urine sediment reveals hematuria, typically with dysmorphic red cells and occasionally with red cell casts; there is a variable degree of proteinuria; and the serum creatinine may be normal or elevated. Hypocomplementemia is common in all types of MPGN. Occasional patients with indolent disease present late in the course at a time when active inflammation has subsided. Such patients may have a bland urine sediment with a variable degree of proteinuria and elevation in serum creatinine. The diagnosis is made by kidney biopsy. (See 'Clinical features' above.)
●Evaluation of the patient with an MPGN lesion – The identification of an MPGN lesion in a kidney biopsy does not establish a specific diagnosis; rather, it should prompt the clinician to pursue a thorough evaluation to determine the underlying cause of the MPGN lesion. The initial step we take in evaluating the patient with an MPGN lesion is to classify the MPGN lesion based upon the immunofluorescence microscopy findings on kidney biopsy (algorithm 1). (See 'Classification of the MPGN lesion' above.)
Subsequent evaluation for the cause of the MPGN lesion is based upon the classification of the MPGN lesion (see 'Subsequent evaluation based upon classification' above):
•In patients who have findings consistent with immune complex-mediated MPGN, we evaluate for infections (such as hepatitis B and C virus and chronic bacterial infections), autoimmune diseases (such as systemic lupus erythematosus). In patients with MPGN and monotypic immunoglobulin deposits, we evaluate for monoclonal gammopathy.
•In patients who have findings consistent with complement-mediated MPGN, we perform an evaluation for activation of the alternative pathway of complement.
•In patients who have findings consistent with MPGN without immunoglobulin or complement deposition, we evaluate for causes of chronic thrombotic microangiopathy (eg, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome) as well as for antiphospholipid antibody syndrome.
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