Membranous Glomerulonephritis

Membranous nephropathy is an autoimmune disorder in which immune complexes deposit along the subepithelial region of the glomerular basement membrane. Antigen-antibody complexes can develop by the production of immune complexes in situ or by deposition of circulating complexes. In the Heymann nephritis model of experimental membranous nephropathy in rats, the intrinsic antigen is a glycoprotein, megalin, synthesized by the glomerular visceral epithelial cells; however, megalin is not present in the human glomerulus. ^[3]

M-type phospholipase A2 receptor (PLA2R) has been identified as the major target antigen in idiopathic membranous nephropathy in adults. Circulating autoantibodies against PLA2R have been found in 70-80% of patients with idiopathic membranous nephropathy. ^{[4, 5]} Anti-PLA2R antibodies are typically not found in patients with secondary membranous nephropathy. ^[4] Anti-PLA2R antibodies have been found in patients with viral infections (eg, hepatitis B, hepatitis C, HIV), but those patients may have had coincidental primary membranous nephropathy. ^[6] Detection of anti-PLA2R antibodies in glomeruli but not in liver parenchyma is a common finding in phatients with membranous nephropathy associated with autoimmune liver disease, suggesting that these autoantibodies are not exclusive to idiopathic membranous nephropathy. ^[7]

Another minor antigen is thrombospondin type 1 domain–containing 7A (THSD7A). Patients who are positive for anti-THSD7A autoantibodies represent a distinct subgroup with this disease and make up approximately 2.5 to 5% of adultts with idiopathic membranous nephropathy. ^{[8, 9]} Hoxha et al reported expression of THSD7A in a gallbladder carcinoma, in a patient who developed membranous nephropathy with anti-THSD7A antibodies, and subsequently found anti-THSD7A antibodies in six other patients with membranous nephropathy and malignant tumors, suggesting that THSD7A production by malignancies is a possible mechanism for membranous nephropathy. ^[10]

Other target antigens detected in patients with membranous nephropathy include the following ^[11] :

• Exostosin 1/exostosin 2 (EXT1/EXT2) - Predominantly present in women; most patients have an underlying autoimmune disease (eg, systemic lupus erythematosus, mixed connective tissue disease)
• Neural EGF-like-1 protein (NELL-1) - Associated with malignancy
• Semaphorin 3B (Sema3B) - Accounts for approximately 15% of pediatric membranous nephropathy cases but only 1-3% of adult cases
• Protocadherin 7 (PCDH7) - Occurs in children and young adults, some of whom have a positive family history

Debiec et al reported that four of nine patients with childhood membranous nephropathy had high levels of circulating anti–bovine serum albumin antibodies and circulating cationic bovine serum albumin. Bovine serum albumin was also seen in immune deposits. It is present in cow's milk and beef protein and can escape the intestinal barrier and cause antibody formation. Its cationic nature allows binding to the anionic glomerular capillary wall with resultant immune complex formation, a parallel to experimental models. This possible environmental trigger could lead to childhood membranous nephropathy, and improvement may be found by eliminating it from the diet. ^[12]

Neutral endopeptidase, a podocyte antigen that can digest biologically active peptides, was identified as the target antigen in a subset of patients with antenatal membranous nephropathy. In these cases, the patients' mothers carried a mutation that rendered them deficient in neutral endopeptidase and they had undergone alloimmunization due to exposure to paternal neutral endopeptidase during pregnancy. ^[13]

Many of the antigens associated with secondary membranous nephropathy are also not known. However, hepatitis B surface antigens and hepatitis E antigens have been identified in immune deposits, as have thyroid antigens in patients with thyroiditis.

The complement membrane attack complex (C5b-9) triggers the biosynthesis of oxygen radical–producing enzymes within the glomerular epithelial cells. The finding of urinary C5b-9 has been suggested as a diagnostic test for following disease activity. ^[14]

C5b-9 in sublytic quantities stimulates podocytes to produce proteases, oxidants, prostanoids, extracellular matrix components, and cytokines, including transforming growth factor-beta (TGF-beta). C5b-9 also causes alterations of the cytoskeleton that lead to an abnormal distribution of slit diaphragm protein and detachment of viable podocytes that are shed into the Bowman space. These events result in disruption of the functional integrity of the glomerular basement membrane and the protein filtration barrier of podocytes with subsequent development of massive proteinuria.

A study by Kuroki et al found that the immune response in idiopathic membranous nephropathy is characterized by alteration of T-cell function to produce Th2 cytokines and increased production of IgG4 by B cells in response to those cytokines. ^[15] A study by Cohen et al pointed to the involvement of B cells in the pathogenesis of membranous nephropathy, possibly as antigen-presenting cells. These authors measured the interstitial expression of CD20 messenger RNA (mRNA) in patients with membranous nephropathy and in control subjects with other kidney diseases. CD20 mRNA expression was significantly higher in patients with membranous nephropathy than in control subjects. B-cell infiltration was confirmed by immunohistochemistry. ^[16]

Frequency

United States

The annual incidence of membranous nephropathy in the United States is estimated at about 12 cases per million population. Membranous nephropathy accounts for approximately 1.9 cases of end-stage kidney disease (ESKD) per million population per year in the US; hence, because only 10-20% of patients with primary membranous nephropathy progress to ESKD, the actual incidence may be as high as 20 cases per million population per year. ^[6]

Primary membranous nephropathy comprises about 80% of cases, while the remainder are secondary to other systemic diseases or exposures (eg, malignancy, infectious disease, autoimmune disorders). ^{[6, 11, 13]} The relative distribution of pathologic causes of nephrotic syndrome varies considerably among various centers, based on population and referral pattern factors.

In the pediatric population, membranous nephropathy is rare but serious. Membranous nephropathy is found in 1-7% of kidney biopsies in children. ^[6] Long-term prognosis is guarded because approximately 50% of patients may have evidence of progressive kidney disease. ^[17]

International

Internationally, the frequency is the same as in the United States, although it is influenced by the prevalence of secondary causes. These include infectious disease such as malaria in Africa and hepatitis B in parts of Asia. ^[18]

Mortality/Morbidity

The course is variable, and patients may be divided into 3 groups of approximately equal size (ie, "rule of thirds").

• Spontaneous complete remission - Kidney function is normal, with or without subsequent relapse.
• Persistent proteinuria of variable degree - Kidney function is normal or impaired but stable.
• Progressive disease, eventually leading to ESKD) - The incidence rate of ESRD is 14% at 5 years, 35% at 10 years, and 41% at 15 years.

Patients in the first and second category die from nonrenal causes.

Race-, sex-, and age-related demographics

Epidemiologic features include the following ^{[13, 18, 6]} :

• Race: In nondiabetic white adults, membranous nephropathy is the most common cause of idiopathic nephrotic syndrome. In some nondiabetic ethnic populations (eg, Blacks, Hispanics), however, membranous nephropathy is less common than focal segmental glomerulosclerosis.
• Sex: Membranous nephropathy has a predilection for males over females, with a male-to-female ratio of 2:1.
• Age: Mean age of onset is from 50 to 60 years. Onset outside the usual range is more likely to be a result of secondary causes.

Overall, patients with primary membranous nephropathy have a good prognosis. Approximately 30% of patients undergo spontaneous remission and another 30% have variable degrees of proteinuria but stable kidney function for many years. However, about 30% progress to kidney failure. Factors at presentation that have been associated with a poor prognosis include male gender, older age, high levels of proteinuria, and abnormal kidney function. ^[18]

Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend using clinical and laboratory criteria for assessing risk of progressive loss of kidney function in patients with membranous nephropathy. On the basis of those criteria, patients can be classified into one of four risk groups (low, moderate, high, or very high), which serves as a guide for therapy. ^[19]

Criteria for low risk are as follows:

• Normal estimated glomerular filtration rate (eGFR) and  proteinuria < 3.5 g/d and serum albumin > 30 g/L or
• Normal eGFR, proteinuria < 3.5 g/d or decreased > 50% after 6 consecutive months of conservative therapy with an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB)

Criteria for moderate risk are as follows:

• Normal eGFR
• Proteinuria > 3.5 g/d and not decreased > 50% after 6 consecutive months of conservative ACEi/ARB therapy
• Not fulfilling high-risk criteria

Criteria for high risk are as follows:

• eGFR < 60 mL/min/1.73 m ² and/or proteinuria > 8 g/d for > 6 months or
• Normal eGFR, proteinuria > 3.5 g/d and not decreased > 50% after 6 consecutive months of conservative ACEi/ARB therapy and at least one of the following:
• Serum albumin < 25 g/L
• Anti-PLA2R antibodies > 50 RU/mL
• Urinary alpha-1 microglobulin > 40 μg/min
• Urinary IgG > 1 μg/min
• Urinary beta-2 microglobulin > 250 mg/d
• Selectivity index > 0.20 (calculated as clearance of IgG/clearance of albumin)

Criteria for very high risk are as follows:

• Life-threatening nephrotic syndrome or
• Rapid deterioration of kidney function not otherwise explained