Membranous Glomerulopathy

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Chapter 506 Membranous Glomerulopathy

Scott K. Van Why, Ellis D. Avner

Membranous glomerulopathy, now commonly called membranous nephropathy (MN), a common cause of nephrotic syndrome in adults, is a rare cause of nephrotic syndrome in children. MN is classified as the primary, idiopathic form, where there is isolated renal disease, or secondary MN, where nephropathy is associated with other identifiable systemic diseases or medications. In children, secondary MN is far more common than primary, idiopathic MN. The most common etiologies of secondary MN are systemic lupus erythematosus (SLE) or chronic infections. Among the latter, chronic hepatitis B infection and congenital syphilis are the best characterized and widely recognized causes of MN. However, other chronic infections have also been associated with MN, including malaria, which is the most common cause of MN worldwide. Certain medications, such as penicillamine and gold, can also cause MN. Rarely, tumors, such as neuroblastoma, or other idiopathic systemic diseases have been associated with MN. Identification of secondary causes of MN is critical, because removal of the offending agent or treatment of the causative disease often leads to resolution of the associated nephropathy and improves patient outcome.

Pathology

Glomeruli have diffuse thickening of the glomerular basement membrane (GBM), without significant cell proliferative changes. Immunofluorescence and electron microscopy typically demonstrate granular deposits of IgG and C3 located on the epithelial side of the GBM in a spikelike pattern. The GBM thickening presumably results from the production of membrane-like material in response to deposition of immune complexes.

Pathogenesis

MN is believed to be caused by in situ immune complex formation. Therefore, antigens from the infectious agents or medications associated with secondary MN directly contribute to the pathogenesis of the renal disease. The causative agents or antigens in the other secondary forms of MN have not been defined. Likewise, the causative antigen in idiopathic MN is not established, but the M-type phospholipase A2 receptor may be a target antigen in idiopathic MN. This receptor, present on normal podocytes, is found to be an antigen present in immune deposits extracted from glomeruli from patients with idiopathic MN. The majority of idiopathic MN patients also demonstrate circulating antibody against this antigen. Specific antigens trigger the onset of primary or secondary MN, but genetic factors significantly influence disease susceptibility and progression.

Clinical Manifestations

In children, membranous glomerulopathy is most common in the 2nd decade of life, but it can occur at any age, including infancy. The disease usually manifests as nephrotic syndrome and accounts for 2-6% of all cases of childhood nephrotic syndrome. Most patients also have microscopic hematuria and only rarely present with gross hematuria. Approximately 20% of children have hypertension at presentation. A subset of patients with MN present with a major venous thrombosis, commonly renal vein thrombosis. This well-known complication of nephrotic syndrome (Chapter 521) is particularly common in patients with MN. Serum C3 and CH50 levels are normal, except in cases of SLE, where levels may be depressed (see Fig. 505-3).

Diagnosis

Membranous glomerulopathy might be suspected on clinical grounds, particularly in the setting of known risk factors for secondary forms of the disease. The diagnosis can only be established by renal biopsy. No serologic test is specific for MN, but finding an active carrier state for hepatitis B or congenital syphilis would make the diagnosis probable in the appropriate clinical setting. Common indications for renal biopsy leading to the diagnosis of MN include presentation with nephrotic syndrome in a child >10 yr or unexplained persistent hematuria with significant proteinuria.

Prognosis and Treatment

The clinical course of idiopathic membranous glomerulopathy is variable. Children presenting with asymptomatic, low-grade proteinuria can enter remission spontaneously. Retrospective reports of children 1-15 yr after diagnosis, treated with a variety of regimens, indicate that 20% progress to chronic renal failure, 40% continue with active disease, and 40% achieve complete remission. Although no controlled trials have been performed in children, immunosuppressive therapy with an extended course of prednisone can be effective in promoting complete resolution of symptoms. The addition of chlorambucil or cyclophosphamide appears to provide further benefit to those not responding to steroids alone. For those unresponsive to immunosuppression, proteinuria can be reduced with angiotensin-converting enzyme inhibitors.

Bibliography

Beck LH, Bonegio RGB, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361:11-21.

Fogo AB, Kashgarian M. Diagnostic atlas of renal pathology. Philadelphia: Saunders; 2005. pp 49–63

Jefferson JA, Couser WG. Membranous nephropathy in the pediatric population. In: Avner ED, Harmon WE, Niaudet P, et al, editors. Pediatric nephrology. ed 6. Heidelburg, Germany: Springer-Verlag; 2009:799-814.

Stanescu HC, Arcos-Burgos M, Medlar A, et al. Risk HLA-DQA1 and PLA2 R1 alleles in idiopathic membranous nephropathy. N Engl J Med. 2011;364:616-626.

Valentini RP, Matoo TK, Kapur G, et al. Membranous glomerulonephritis: treatment response and outcome in children. Pediatr Nephrol. 2009;24:301-308.

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