MEMBRANOUS
NEPHROPATHY
Membranous nephropathy (MN) is one of the most common causes of
nephrotic syndrome in adults. It is named for the major histologic finding of
diffuse glomerular basement membrane (GBM) thickening. The epidemiology and
overall incidence of this disease has remained constant over several decades,
with a peak incidence between 30 and 50 years of age.
In most cases MN is a primary
phenomenon. About one quarter of cases, however, occur secondary to systemic
diseases or infections. The major causes include systemic lupus erythematosus
(SLE), rheumatoid arthritis, Sjögren syndrome, Hashimoto thyroiditis, viral
hepatitis infection (hepatitis B and, less commonly, hepatitis C),
hematopoietic stem cell transplantation, and solid tumors (e.g., lung, colon,
breast, kidney carcinomas). Some medications such as gold, penicillamine,
NSAIDs, and antitumor necrosis factor agents have
also been implicated.
PATHOPHYSIOLOGY
Primary MN occurs when circulating
antibodies permeate the GBM and form immune complexes with epitopes on podocyte
membranes. Although lymphocytes do not have access to this space, formation of
complement C5b-C9 membrane attack complexes inflicts significant damage on
podocytes. As a result, foot process effacement occurs, and the glomerular
capillary walls are no longer capable of excluding proteins from the urinary
space. In addition, the damaged podocytes secrete additional extracellular
material that leads to expansion of the GBM.
For several decades, the specific
podocyte epitope responsible for the above processes was unknown. During this
time, however, it was discovered that antibodies targeting megalin, a podocyte
membrane protein, produced a nearly identical disease in rats known as Heymann
nephritis. Although this finding offered insights into the basic mechanism for
MN, it did not clarify the relevant epitope in humans because megalin is not
expressed on human podocytes.
More recent research, however,
identified the M-type phospholipase A2 receptor (PLA2R), found on the surface of
podocytes, as a major antigen in primary MN. In one series, antibodies
targeting this transmem brane protein were identified in approximately
70% of patients with primary MN. In contrast, these antibodies were not
identified in patients with secondary MN or healthy controls.
Secondary MN appears to result from
subepithelial deposits of circulating immune complexes. Presumably, the
antigens involved in the various disease states that cause secondary MN double-stranded
DNA in SLE; hepatitis B antigen; carcinoembryonic antigen, prostate specific
antigen, and many others in malignancy; thyroglobulin in thyroiditis;
treponemal antigen, and many others in syphilis spur formation of immune
complexes, which deposit in the glomerulus. In secondary MN these immune
complexes are found in the subepithelial space, which leads to podocyte injury.
Unlike in primary MN, however, immune complexes may also deposit in the
mesangium and extraglomerular sites.
PRESENTATION AND DIAGNOSIS
The classic presentation of MN is
nephrotic syndrome (see Plate 4-7) with an insidious onset. Patients typically describe
slowly progressive lower extremity edema that, in some cases, has advanced to
overt anasarca. Laboratory examination of serum and urine reveals proteinuria,
hypoalbuminemia, and hyperlipidemia. Renal function, as inferred from serum
creatinine concentration, is usually intact. The degree of proteinuria in MN
patients is variable, ranging from subnephrotic (i.e., less than 3.5 g/day) to
more than 20 g/day. Some patients may have completely asymptomatic proteinuria.
Patients with MN are at increased
risk of renal vein thrombosis, even among other patients with nephrotic
syndrome. This complication affects up to one in five patients in some series.
In general, the heavier the proteinuria and lower the serum albumin, the higher
the risk for thrombotic complications.
MN can only be diagnosed based on
histopathologic findings. Thus in adults with unexplained nephrotic syndrome,
renal biopsy must be performed. In MN, light microscopy reveals
diffuse GBM thickening, which is especially prominent with silver stains. The
pathogenetic immune complexes are not visible at this resolution; however, the
growing GBM forms “spikes” between these complexes, which may be seen instead.
In primary MN there are generally no cellular infiltrates, since the immune
complexes form in the subepithelium and are thus protected from the
circulation. In secondary MN, however, infiltrates may occur because circulating
immune complexes also deposit in the mesangium.
Immunofluorescence reveals diffuse
granular staining for IgG and C3 along the GBM. Using electron microscopy,
effacement of podocyte foot processes may be seen. In addition, the
subepithelial immune complexes are visible as electron-dense deposits. These
are limited to the subepithelium in primary MN but may also be visible in the
mesangium in secondary disease. The presence of endothelial tubulo-reticular
inclusions suggests SLE-related disease.
If biopsy confirms MN, patients
should be evaluated for the most common causes of secondary disease, especially
if there are also suggestive histologic findings. The most important laboratory
tests include antinuclear and anti-dsDNA antibodies for SLE; hepatitis B and C
serologies; and rapid plasma reagin screening for syphilis. In addition, all
patients above the age of 40 with confirmed MN should undergo screening for
malignancies because the incidence is about 5% to 10% in this population,
rising as high as 20% in patients over 60 years old. Even patients
with a negative initial workup should continue to undergo surveillance because
malignancies may not appear until months or even years after the onset of
nephrotic syndrome.
TREATMENT
All patients should be placed on a
renin-angiotensin system blocker (e.g., ACE inhibitor) and cholesterol-lowering
medication, such as a statin, for as long as the proteinuria continues. Edema
can be treated as needed with diuretic therapy, and all patients should be
encouraged to adopt a low-salt diet.
In idiopathic MN, the need for immunosuppression
depends on the risk of disease progression. Patients with subnephrotic
proteinuria, for example, often experience spontaneous remission and should
there- fore receive only the conservative treatments listed above.
Patients with very heavy
proteinuria (more than 8 to 9 g/day), in contrast, will likely develop
progressive chronic kidney disease if they do not receive immunosuppressive
agents. Patients with intermediary proteinuria (between 3.5 to 8 g/day) should
receive immunosuppressive agents if proteinuria does not fall below 3.5 g/day
after 6 months of conservative management.
Several immunosuppressive agents
may be used to treat primary MN. The two leading therapies are alkylating
agents (cyclophosphamide or chlorambucil) and calcineurin inhibitors
(cyclosporine or tacrolimus), either of which is given in combination with oral
or intravenous corticosteroids. Recently, other agents such as rituximab, ACTH,
and mycophenolate mofetil have also shown promising results, particularly in
cases refractory to initial therapeutic attempts.
In secondary MN, treatment centers
on removal of the underlying cause, after which there is often a complete
remission of proteinuria within several months.
PROGNOSIS
Patients with idiopathic MN who
experience either spontaneous or drug-induced remission have an excellent
prognosis, and the majority of patients who receive immunosuppression achieve
complete or partial remission. Relapse, however, occurs in up to 30%, requiring
repeat rounds of immunosuppression.
The patients who do not achieve
long-term remission may experience a progressive, sometimes rapid, decline in
renal function that can progress to ESRD. If a transplant is performed, the
risk of MN recurring in the allograft is approximately 10% to 15%.
