Membranous nephritis

# Overview
Membranous nephropathy (MN) or membranous glomerulonephritis (MGN) is a common glomerulonephritis that usually presents with nephrotic-range proteinuria, edema, and hypertension.  MN is generally classified as primary (idiopathic) or secondary to other systemic disease, such as infections, malignancies, vasculitides etc. Primary MN has been recently associated with a newly discovered phospholipase A2 receptor (PLA2R) nephrotigenic antigen on the membrane surface of glomerular podocytes and the presence of anti-PLA2R antibodies. Kidney biopsy remains the gold standard for the diagnosis of MN, showing subepithelial deposits with capillary wall thickening and IgG deposition under immunofluorescence. While MN is widely considered a chronic condition with a waxing and waning course, it is usually self-limited in the majority of the cases. Heavy proteinuria, a significant marker of prognosis, indicates the need for intervention.

# Historical Perspective
The term membranous nephropathy was first coined by Elexious T. Bell, a pathologist, in 1946 to describe a specific disease entity characterized by gradual-onset proteinuria and edema under Ellis type II glomerulonephritis, a classification by Arthur Ellis based on clinical and histopathological findings. In 1957, David Jones used acid-silver methenamine, also known as Jones stain, to demonstrate that membranous nephropathy must be considered a unique glomerulonephritis due to the characteristic presence of capillary wall thickening and disruption of basement membrane. In 1959, Movat and McGregor used electron microscopy to identify subepithelial deposits in membranous nephropathy, based on earlier findings by Coons and Kaplan in 1950, Farquhar, and Mellors in 1957. It was not until 2009 when Beck and colleagues discovered that the presence of antibodies against the nephritogenic phospholipase A2 receptor (PLA2R) is associated with the pathogenesis of the disease.

# Epidemiology and demographics
Membranous nephropathy or membranous glomerulonephritis (MGN) has always been considered the most common glomerulonephritis associated with nephrotic syndrome, defined as severe proteinuria > 3.5 g/d, accounting for approximately 36% of cases. Only recently, new data is suggesting that focal segmental glomerulosclerosis (FSGS) may have surpassed MGN as the leading cause of unexplained nephrotic syndrome. In general, MGN may be a disease of any age, any gender, and any ethnicity. However, the peak incidence of primary MN is between 40 and 50 years of age; and it is very rarely seen in children. There is a slight male predominance to the disease and it is thought to be more common among Caucasians. In 1996, Korbet and colleagues showed that among 340 patients with primary glomerulonephritis presenting with nephrotic syndrome over 20 years, MGN accounts for 24% of cases in African-American patients vs. 36% of cases in Caucasian patients. The majority of the patients present with mild proteinuria; but 60% of those eventually progress into nephrotic-range proteinuria within 1-2 years.
MGN is considered very rare in the pediatric population. Only 1-4% of all MGN is among children aged 1-12 years, and MGN comprises only 1.5% of all cases of nephrotic syndromes among children. However, the incidence of MGN increases to 22% among patients aged 13-19 years. Among adult patients, most cases of MGN are idiopathic. Only 20-30% of cases are due to secondary causes, such as infections, systemic illnesses, cancers, and medications. Secondary MGN, however, may have different age and geographic distributions. Secondary causes, such as hepatitis B infection, are in fact much more common in the pediatric age groups, reaching up to 35-75% of all cases of MGN.

# Pathophysiology
Early description of the pathophysiology of membranous nephropathy noted that the disease might be due to an auto-antibody production against an antigen on podocytes surfaces. In 2009, Beck and colleagues discovered that M-type phospholipase A2 receptor (PLA2R) protein is a nephritogenic antigen. It is currently believed that anti-PLA2R is present in approximately 80% of patients with primary membranous nephropathy and to a much lesser extent in patients with secondary membranous nephropathy in patients, especially in patients with hepatitis B and malignancies. PLA2R1 is a 185-KDa glycoprotein expressed on the podocyte membrane surface. Physiologically, its role has not been confirmed, but is presumed to be involved in the aging of the cell through the p53 pathway. It contains several characteristic domains:
- Extracellular domain: Long domains with cysteine-rich head and a nephritogenic epitope at a methionine-rich terminal
- Fibronectin type II-like repeat domains
- Repeated carbohydrate-recognition domains
- Membrane-spanning domains
- Intracellular domains
The nephritogenic epitope in the extracellular domain is destroyed when the cysteine-cysteine disulfide bridges are disrupted.  Control of immune response by anti-PLA2R antibodies is maintained genetically by PLA2R1 gene locus at chromosome 2 and HLA-DQA1 and DQB1 on chromosome 6. Peptides from PLA2R1 bind HLA-DQA1-expressing-antigen-presenting cells activate T cells and subsequently cause the production of antibodies, such as IgG4, by Th2 cytokine activation. that contribute to clinical manifestations, such as proteinuria. Proteinuria itself  has been also associated with unique molecular findings, such as formation of membrane attack complex (C5b-C9) and further T-cell activation (CD8+).
Presence of immunoglobulin subclass may have important pathological effects.
- IgG4: Associated with primary membranous nephropathy. It is presumed to have a protective effect when IgG1 is present because it acts against the formation of immune complexes.
- IgG1, IgG2, and IgG3: Associated with secondary membranous nephropathy. Their role seems to be pathogenic.
The presence of anti-PLA2R has been correlated with clinical manifestations, prognosis, and recurrence of disease in membranous nephropathy.
Several hypotheses have been postulated as to why a small number of patients with primary membranous nephropathy and the majority of those with secondary membranous nephropathy do not have detectable anti-PLA2R antibodies.  These factors are summarized as follows:
- Poorly sensitive assays used for detection
- Heterogeneous conformation of PLA2R epitope
- Disappearance of antibodies spontaneously or due to treatment
- Involvement of other nephritogenic antigens
Other antigens have been implicated in the disease and may have a role in the pathogenesis of membranous nephropathy. However, these antigens still require further validation.:
- Neutral endopeptidase
- Superoxide dismutase
- Aldose reductase
- Alpha-enolase
- Cationic serum albumin
- Renal tubular antigens (megalin)

# Causes

## Primary Membranous Nephropathy
Most cases of MGN are primary. The cause is thus unknown and they are designated as idiopathic.

## Secondary Membranous Nephropathy
Less commonly in adults, MGN may be associated with secondary etiologies. According to the National Kidney Foundation (NKF) Kidney Disease  Improving Global Outcomes (KDIGO) published in 2012, the list of secondary causes of MGN is listed as shown below.
The prevalence of secondary MGN is more common among children, comprising up to 35-75% of all MGN cases in this age group. The most common secondary etiology to pediatric MGN is hepatitis B virus.

### Autoimmune Etiologies
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Mixed connective tissue disease
- Dermatomyositis
- Ankylosing spondylitis
- Systemic sclerosis
- Myasthenia gravis
- Bullous pemphigoid
- Autoimmune thyroid disease
- Sjogrens syndrome
- Temporal arteritis
- Crohns disease
- Graft-vs-host disease

### Infectious Etiologies
- Hepatitis B
- Hepatitis C
- HIV
- Malaria
- EBV
- Schistosomiasis
- Filariasis
- Syphilis
- Enterococcal endocarditis
- Hydatid disease
- Leprosy

### Tumors
- Lung cancer
- Colon cancer
- Breast cancer
- Gastric cancer
- Ovarian cancer
- Prostate cancer
- Orophayngeal or esophageal cancer
- Hodgkin's lymphoma
- Non-Hodgkin's lymphoma
- Chronic lymphocytic leukemia
- Mesothelioma
- Melanoma
- Wilm's tumor
- Hepatic adenoma
- Angiolymphatic hyperplasia
- Schwannoma
- Neuroblastoma
- Adrenal ganglioneuroma

### Medications
- Penicillamine
- Bucillamine
- Captopril
- Probenicid
- Trimethadione
- NSAID
- Cyclooxygenase 2 inhibitors
- Clopidogrel
- Lithium

### Other Toxins
- Gold salts
- Mercury
- Formaldehyde
- Hydrocarbon

### Other Etiologies
- Diabetes mellitus
- Sarcoidosis
- Sickle cell disease
- Polycystic kidney disease
- Alpha-1-antitryprsin deficiency
- Weber-Christian disease
- Primary biliary cirrhosis
- Systemic mastocytosis
- Guillain-Barre syndrome
- Urticarial vasculitis
- Hemolytic uremic syndrome
- Dermatitis herpetiformis
- Myelodysplasia

# Classification
The classification of MGN is based on the presence of electron-dense deposits on electron microscopy. This staging has been first described by Ehrenreich and Churg in 1963.

# Differentiating membranous nephropathy from other diseases
Other common forms of glomerulonephritis that present with nephrotic syndrome are common differential diagnoses of membranous nephropathy.
- Minimal change disease
- Focal segmental Glomerulosclerosis
- Membranoproliferative glomerulonephritis

# Diagnosis
Kidney biopsy is the gold standard for the diagnosis of MGN. On light microscopy, kidney biopsy typically shows subepithelial despoits with capillary wall thickening and normal cellularity. Immunofluorescence shows IgG and C3 deposits along capillary walls. Electron microscopy shows exclusively subepithelial deposits between podocyte foot processes.
Subtype of IgG present on immunofluorescence may be helpful in differentiating idiopathic vs. secondary causes of MGN. In primary idiopathic MGN, the IgG4 subtype of IgG is most commonly seen whereas IgG1, 2, and 3 are more commonly seen in secondary MGN.
Furthermore, the location of the deposits may also provide clues on the diagnosis. While deposits in primary MGN are exclusively seen in the subepithelial region, deposits in secondary MGN may involve subepithelial and more likely subendothelial regions of the capillary wall.
A repeat biopsy may only be necessary if deteriorating kidney function ensues with doubling of serum creatinine occurs over 1-2 months while proteinuria remains below 15 g/d.

# Natural History
Studies pertaining to MGN mostly involve patients with nephrotic-range proteinuria. This is because it is widely accepted that patients with mild proteinuria do not require any intervention and most likely will remit spontaneously.
MGN is considered a chronic progressive disease with episodic relapses and remissions. Spontaneous remission within 2 years is seen in approximately 30-35% of patients with a survival rate at 10 years reaching 70% among white patients who present with MGN and nephrotic-range proteinuria. In 2010, Polanco and colleagues showed that spontaneous remission in MGN occurs in a mean time of 14.7 +/- 11.4 months.
Approximately 20% of patients with nephrotic-range MGN experience spontaneous remission. The relapse rate among patients with idiopathic MGN is approximately 15-30%. Fifty percent of patients continue to have persistent proteinuria.
In patients who are in remission, progression to ESRD is virtually nill. In patients with persistent proteinuria, however, approximately 35% of those progress into ESRD within 10 years. These patients are also more susceptible to other non-renal complications, such as cardiovascular disease and infections.

# Prognosis
The degree of presenting proteinuria is considered the most important prognostic factor. Quantification of proteinuria is of major prognostic significance because proteinuria seems to have a dose-dependent effect on prognosis and on rates of spontaneous remission. As such, mild non-nephrotic proteinuria is associated with increased chances for spontaneous remission. The rate of remssion may be delayed to several years, especially when proteinuria becomes in the sub-nephrotic range; the rate of proteinuria reduction might be very slow and occur over several years before completely normal renal function is restored. On the other hand, it is unlikely that patients with heavy proteinuria to experience spontaneous remission.
Furthermore, the decrease in proteinuria from baseline during the first 6-12 months, as shown by Polanco et al. in 2010, to more than 50% has been shown to be of favorable outcome in patients with idiopathic MGN. Age and gender have also been shown to be consistently associated with prognosis. Age < 50 years and female gender seem to be associated with spontaneous remission.
As such, the 3 main elements that favor good prognosis are as follows:
Ever since the description of PLA2R in 2009, serum levels of anti-PLA2R antibodies have been implicated in clinical manifestations, prognosis, and recurrence of disease in patients with membranous nephropathy. Decreasing levels also seem to correlate with resolution of disease.
Interestingly, histopathological findings of MGN does not seem to be highly emphasized in the literature as a prognostic factor as seen in other glomerulonephritides, despite presence of low-quality evidence to support such hypothesis. However, large extent of fibrosis and sclerosis seen on pathology and specific heterogeneous configurations (vs. synchronous deposits) of immune deposits have been associated with poorer prognosis.
Other less significant factors that have been shown to be associated with spontaneous remission:
- Renal insufficiency > 1.5 mg/dL
- Presence of urinary alpha-1-microglobulin or beta-2-microglobulin
- Presence of urinary IgG and IgM
- Presence of hypertension
- Histologic evidence of interstitial fibrosis, tubular atrophy, and segmental glomerular sclerosis.
- Persistently elevated urinary C5b-9
Treatment may significantly alter prognosis in MGN; where use of ACE-inhibitors or ARB and the consequent reduction in proteinuria are key to improve prognosis and renal outcomes

# Management

## Goals of Management
- Induction of remission or partial remission
- Assessment of need to treat beyond conservative treatment based on clinical risk stratification
- Prevention of progression into ESRD
- Maintenance of remission
- Prevention of associated complications from disease or treatment, such as renal vein thrombosis, interstitial nephritis, or crescent formation
- Distinguishing relapse from failure of therapy
Since approximately 30% of patients achieve spontaneous remission within 6 months, it is plausible to defer any particular treatment until 6 months, if no complications occur during the observation period. Meanwhile, patients may only be maintained by mere reduction of proteinuria using ACE-I or ARBs.
Stratification of patients based on proteinuria and renal function is important for appropriate management:
According to the National Kidney Foundation (NKF) Kidney Disease  Improving Global Outcomes (KDIGO) in 2012, the current recommendation for initiation of therapy and first relapse following successful initial therapy in MGN consists of the Ponticelli regimen for adults and pediatric patients. For adults, the regimen includes alternating doses of corticosteroids, especially cyclophosphamide and alkylating agents. Unlike adults, it is recommended that children receive the regimen only once. 
The regimen is contraindicated only if the patient has an untreated infection, such as HIV, HBV, HCV, tuberculosis etc., cancers, urinary retention, serum creatinine > 3.5 mg/dL, pre-existing leukopenia < 4000/mm3, or may be unable to perform proper monitoring during and after therapy or does not wish to receive the regimen.

## Recommended Ponticelli Regimen
Months 1, 3, and 5
- Methylprednisolone
Initial Treatment
Initial Route: Intravenous (IV)
Initial Dose: 1 g daily
Initial Duration: 3 doses
Treatment After Initial Treatment
Second Route: Per Os (PO)
Second Dose: 0.5 mg/kg/d
Second Duration: 27 days
- Initial Treatment
Initial Route: Intravenous (IV)
Initial Dose: 1 g daily
Initial Duration: 3 doses
- Initial Route: Intravenous (IV)
- Initial Dose: 1 g daily
- Initial Duration: 3 doses
- Treatment After Initial Treatment
Second Route: Per Os (PO)
Second Dose: 0.5 mg/kg/d
Second Duration: 27 days
- Second Route: Per Os (PO)
- Second Dose: 0.5 mg/kg/d
- Second Duration: 27 days
Months 2, 4, and 6
- Cyclophosphamde
Route: PO
Dose: 2 mg/kg/d adjusted to age and eGFR
Duration: 30 days
- Route: PO
- Dose: 2 mg/kg/d adjusted to age and eGFR
- Duration: 30 days
Cyclophosphamide may be substituted by chlorambucil at a dose of 0.15-0.2 mg/kg/d, adjusted to age and eGFR. However, chlorambucil is associated with a worse toxicity profile.
Necessary Work-Up During "Ponticelli Regimen"
- White blood cell (WBC) count
- Serum creatinine
- Serum albumin
- Urinary protein excretion
Monitoring should be done q2w for the first 2 months, then once per month for 6 months. If total WBC count is below 3500/mm3, alkylating agents must be discontinued until the patients WBC count is restored to above 4000/mm3.
If albumin falls below 2.5 g/dl with the presence of other thrombosis risk factors, patient are recommended to be started on anticoagulant prophylaxis with warfarin therapy.

## Alternative Regimen
If the Ponticelli regimen is contraindicated or if the patients condition is resistant to the initial regimen, the use of calcineurin inhibitors is thus recommended. The following regimens may be used for 6 months and are to be discontinued if no complete or partial remissions are achieved.
Regimen 1
- Cyclosporine
Route: PO
Dose: 3.5-5 mg/kg/d in 2 equally divided doses 12 hours apart. To start at 3.5 mg/kg/d dose and gradually increase only if necessary
Duration: 6 months
- Route: PO
- Dose: 3.5-5 mg/kg/d in 2 equally divided doses 12 hours apart. To start at 3.5 mg/kg/d dose and gradually increase only if necessary
- Duration: 6 months
- Prednisone
Route: PO
Dose: 0.15 mg/kg/d in 2 equally divided doses 12 hours apart, to be given with cyclosporine
Duration: 6 months
- Route: PO
- Dose: 0.15 mg/kg/d in 2 equally divided doses 12 hours apart, to be given with cyclosporine
- Duration: 6 months
Regimen 2
- Tacrolimus
Route: PO
Dose: 0.05-0.075 mg/kg/d in 2 equally divided doses 12 hours apart. To start at 0.05 mg/kg/d dose and gradually increase only if necessary
Duration: 6-12 months
- Route: PO
- Dose: 0.05-0.075 mg/kg/d in 2 equally divided doses 12 hours apart. To start at 0.05 mg/kg/d dose and gradually increase only if necessary
- Duration: 6-12 months
Maintenance Dose
The use of calcineurin inhibitors (CNI) may be decreased q4-8 weeks by 50% for at least 12 months only if the patient continues to be in remission and if no nephrotoxic side effects of the medications occur.
Necessary Work-Up During Alternative Regimen
During therapy, CNI blood levels should be performed initially and when serum creatinine is elevated to levels more than 20% during therapy.

## Novel Pharmacologic Therapy
Other pharmacologic therapy that still require clinical trials:
- Mycofenolate Mofetil (MMF)
- Rituximab
- Eculizumab
- ATCH