Article Update

Saturday, May 16, 2020


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.

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.

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.

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.

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%.

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