MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
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.
Pathophysiology
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.
Treatment
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.
Prognosis
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.
