Membranoproliferative glomerulonephritis (MPGN) is a pattern of glomerular disease that can occur either as an idiopathic, primary phenomenon or secondary to numerous systemic conditions. It is a rare disorder, and its incidence appears to be decreasing, particularly in the developed world.
MPGN is sometimes known as “mesangiocapillary glomerulonephritis” because the major histologic features include mesangial expansion, thickening of glomerular capillaries, and interposition of mesangial matrix into the glomerular basement membrane. Alternatively, because of the lobular appearance of the glomerulus following mesangial expansion, MPGN is sometimes termed “lobular glomerulonephritis.” These morphologic changes are responsible for the major symptoms of this disorder, which include hematuria and a variable degree of proteinuria.
There are three subtypes of MPGN, which are distinguished based on their electron microscopy features:
Type I MPGN immune complex deposits seen mainly in the glomerular capillary subendothelium and mesangium.
Type II MPGN (Dense Deposit Disease) diffuse, electron-dense, intramembranous deposits seen within the glomerular, tubular, and arteriolar basement membranes
T pe III MPGN a morphologic variant of type I MPGN with prominent subepithelial deposits.
Activation of the complement system appears to be the central, unifying pathophysiologic mechanism in all MPGN subtypes. Indeed, “hypocomplementemic glo- merulonephritis” is yet another term often used to imply MPGN. The speciﬁc cause of complement activation, however, appears to differ among the subtypes.
In type I MPGN, the most common form, immune complexes deposit in the mesangium and glomerular subendothelium, then activate the classical complement pathway. These immune complexes can be either idiopathic or secondary to other disease processes, including chronic infections (chronic hepatitis C with or without detectable cryoglobulinemia, chronic hepatitis B, sub- acute bacterial endocarditis, infected ventriculoatrial shunt, malaria, schistosomiasis), autoimmune disease (systemic lupus erythematosus, Sjögren syndrome), and hematologic disorders (essential cryoglobulinemia, Waldenström macroglobulinemia, chronic lymphocytic leukemia).
The exact proportion of idiopathic versus secondary type I MPGN is difﬁcult to estimate; however, in recent years, it has been appreciated that HCV and cryoglobulinemia are responsible for many of the cases that had previously been considered idiopathic. Cryoglobulins are proteins that precipitate when blood is cooled below 37° C. They mostly consist of immunoglobulin and complement components, and they are found in conditions of chronic immune stimulation or lymphoproliferation, such as hepatitis C infection, HIV infection, and lymphoproliferative disorders.
In DDD, complement activation is antibody-independent and instead occurs in the setting of dysregulated activation. Moreover, complement activation follows the alternative rather than classic pathway. Complement activation occurs by two major mechanisms. At least 80% of patients produce an autoantibody known as C3 nephritic factor (C3NeF), which stabilizes C3 convertase. In a smaller fraction of patients, there is functional loss of factor H, the major inhibitor of C3 convertase, because of either genetic mutations or antifactor H anti-bodies. Both C3Nef and loss of factor H cause chronic overactivation of C3 convertase, with subsequent complement activation and C3 consumption.
The pathogenesis of type III MPGN appears similar to that of type I MPGN. Indeed, many consider type III MPGN to be a morphologic variant of type I, although the pathogenetic mechanisms underlying the differences seen on electron microscopy remain poorly understood.
In all MPGN types, complement activation drives injury to the glomerular capillaries and mesangium. Inﬂammatory cells, especially monocytes, may be recruited to various degrees and contribute to the damage. Following inﬂammation, reactive processes of cellular proliferation and repair cause mesangial matrix expansion, as well as duplication of the glomerular basement membrane. By disrupting the normal components of the ﬁltration barrier, these inﬂammatory processes result in hematuria and proteinuria.
Presentation and Diagnosis
The different MPGN subtypes generally present in childhood and young adulthood, and all are essentially indistinguishable with respect to their renal manifestations. The most common presentation of MPGN is the nephrotic syndrome, which is present in approximately half of patients. Even in those without overt nephrotic syndrome, a varying degree of proteinuria is almost always present. Microscopic hematuria is found in nearly 90% of cases, usually featuring dysmorphic erythrocytes but occasionally red blood cell casts as well. Up to 20% of patients may have acute glomerulonephritis.
One extrarenal manifestation particular to DDD is the development of ocular deposits known as drusen. These whitish-yellow deposits lie beneath the retinal pigment epithelium and can be seen during funduscopic examination. These lesions are also characteristic of age-related macular degeneration. The reason for drusen formation in DDD is not entirely clear; however, drusen have been found to have similar oligosaccharide composition to the electron-dense glomerular deposits, implying a possible common pathogenesis. In addition, DDD is sometimes associated with acquired partial lipodystrophy (APL), a syndrome characterized by the loss of subcutaneous fat in the upper half of the body and C3 hypocomplementemia. This phenomenon, frequently associated with C3NeF, may reﬂect complement dependent lysis of adipocytes expressing high amounts of complement components, such as factor D (also known as adipsin).
In any patient for whom MPGN is on the differential, complement levels should be assessed—speciﬁcally, C3, C4, and CH50 (total hemolytic complement, a functional assay of the complete cascade). The ﬁnding of hypocomplementemia is generally useful in the assessment of glomerulonephritis because it is present in only a few types: MPGN, cryoglobulinemic vasculitis, lupus nephritis, and postinfectious glomerulonephritis. In types I and III MPGN, where the classic pathway is activated, the typical pattern is a low or normal C3, low C4, and low CH50. In DDD, characteristically C3 is markedly decreased and CH50 is also low, whereas C4 is normal, which reﬂects activation of the alternative pathway. While these patterns are helpful, it must be noted that they are neither sensitive nor speciﬁc for the diagnosis of MPGN or its subtypes.
The deﬁnitive diagnosis of MPGN can only be established based on histopathologic ﬁndings. The general pattern of MPGN is usually readily recognized on light microscopy, although this modality cannot differentiate between the subtypes. Two basic features are characteristic: (1) mesangial proliferation with hypercellularity and/or matrix expansion, often leading to pronounced lobulation of the glomerulus, and (2) thickening of the capillary basement membrane. Capillary loop thickening and interposition of matrix or inﬂammatory cells often results in a splitting or duplication of the basement membrane, which assumes the classic double-contoured “tram track” appearance. An exudative form of MPGN can also be seen, especially in cryoglobulinemic glomerulonephritis, which is characterized by massive glomerular inﬁltration by inﬂammatory cells, particularly monocytes.
On immunoﬂuorescence, types I and III MPGN usually show prominent granular capillary wall staining with C3, variable amounts of IgG and IgM, and sometimes C1q and C4. In contrast, in DDD the capillary wall typically stains with C3 in isolation.
The deﬁnitive distinction between MPGN sub- types can only be made with electron microscopy. In type I MPGN, immune deposits are seen in the subendothelium, whereas in type III they are also seen in the subepithelium. In DDD, pathognomonic electron-dense, intramembranous deposits are seen in the glomerular basement membrane. In many cases, these deposits are also present in the basement mem- branes of the tubules and arterioles. While the exact composition of the deposits has not been determined, they appear to contain glycoproteins similar to normal glomerular basement membrane, and they do not appear to contain antigenic material, immunoglobulins, or complement. In all subtypes, podocyte foot processes appear diffusely effaced.
If type I MPGN is diagnosed, the clinician must undertake a careful evaluation to rule out potentially causative systemic disease. This is particularly important because some of those diseases, such as parasitic infections, may be otherwise subclinical but amenable to treatment. All patients should be tested for hepatitis C and B, as well as for cryoglobulins. A negative HCV-antibody test in the presence of cryoglobulins should be interpreted with caution because the antibodies to virus may complex with the cryoglobulins and become undetectable by standard assays. If HCV is ruled out, tests for other chronic infections, autoimmune disease, or dysproteinemias should follow as appropriate. Any patient with a ventriculoatrial shunt should be considered infected until proven otherwise. Idiopathic type I MPGN should remain a diagnosis of exclusion.
If DDD is diagnosed, an assay for C3NeF should be sent and a screen for factor H mutations and activity should be performed. While none of these tests are diagnostic, they are crucial for planning therapy.
Types I/III MPGN. If an underlying cause has been identiﬁed, it should be the primary focus of initial management. Eradication of chronic infection, in particular, may lead to complete resolution of the renal lesion. In HCV-associated MPGN, antiviral treatment that results in successful suppression of viral load has been shown to correlate with stabilization or regression of the renal manifestations and improvement of proteinuria. For severe disease, antiviral treatment is often accompanied by therapies aimed at reduction of circulating immune complexes, including plasmapheresis, corticosteroids, cytotoxic drugs, and rituximab.
In idiopathic disease, patients with subnephrotic proteinuria and lack of progressive renal dysfunction may be managed using conservative measures alone. These include blood pressure control and renin-angiotensin blockade to limit proteinuria. If present, hyperlipidemia should also be managed. Patients with progressive disease, in contrast, should have a trial of immunosuppression. In children, at least one reasonably large randomized con- trolled trial demonstrated that a course of prednisone preserved renal function better than placebo. This beneﬁt, however, was offset by signiﬁcant corticosteroid toxicity. The studies on corticosteroids in adults have been less encouraging, and it is essential that HCV be ruled out before this therapy is attempted. Various combinations of cytotoxic and immunosuppressant drugs have been used with some success, but none has been rigorously evaluated. Antiplatelet and antithrombotic agents have also been used—speciﬁcally warfarin, aspirin, and dipyridamole—with some short-term success reported in small trials. This treatment strategy is based on the postulated contribution of platelet activation to the inﬂammatory process in MPGN.
DDD. The treatment strategy depends on the identiﬁed cause. If C3NeF is identiﬁed, strategies to remove it include plasmapheresis, IVIg, and B-cell suppression, but success has been limited. For those few patients with identiﬁed factor H mutations, plasma exchange to replace the deﬁcient complement factor can stabilize renal function and prevent progression to ESRD. The role of complement inhibitors (e.g., eculizumab) is under investigation.
Outcomes in idiopathic disease are poor. More than 60% of patients with type I MPGN will progress to ESRD within 10 years of diagnosis. For DDD, the picture is even more grim, with ESRD usually occur- ring within 4 years of diagnosis. In all MPGN types, signs that portend a poorer prognosis include nephrotic syndrome, reduced GFR, and advanced tubulointerstitial disease. Complement levels do not correlate well with prognosis.
For patients who reach ESRD, renal transplant may be performed, but recurrence in the allograft is common unless the underlying cause has been addressed. MPGN type I has been documented to recur in 30% to 77% of allografts, leading to graft loss in 17% to 50% of cases. For DDD the prognosis is even worse, with virtually all transplanted patients experiencing recurrence and at least half eventually losing the graft as a result.