Membranous nephritis

(Redirected from Membranous nephropathy)
Jump to: navigation, search
Membranous nephritis
ICD-10 N00-N08, with .2 suffix
ICD-9 581.1, 582.1 , 583.1
DiseasesDB 7970
MedlinePlus 000472
eMedicine med/885 

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, Serge Korjian

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[1], 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.[1] 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.[2] In 1959, Movat and McGregor used electron microscopy to identify subepithelial deposits in membranous nephropathy[3], based on earlier findings by Coons and Kaplan in 1950[4], Farquhar[5], and Mellors[6] in 1957. It was not until 2009 when Beck and colleagues[7] 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.[8] Only recently, new data is suggesting that focal segmental glomerulosclerosis (FSGS) may have surpassed MGN as the leading cause of unexplained nephrotic syndrome.[8] 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[9]; 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.[9] 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.[10] 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.[11][12] However, the incidence of MGN increases to 22% among patients aged 13-19 years.[12][13] Among adult patients, most cases of MGN are idiopathic.[14] Only 20-30% of cases are due to secondary causes, such as infections, systemic illnesses, cancers, and medications.[14] Secondary MGN, however, may have different age and geographic distributions.[15][16][17][18][19] 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.[20][11]

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.[1][21][22] In 2009, Beck and colleagues[7] 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[7][23][24][25][26] and to a much lesser extent in patients with secondary membranous nephropathy in patients, especially in patients with hepatitis B and malignancies.[26] PLA2R1 is a 185-KDa glycoprotein expressed on the podocyte membrane surface.[7][27] 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[27]:

  • 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.[7] 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.[28] 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.[29][30][31] 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+).[29][30]


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.[22][32]
  • IgG1, IgG2, and IgG3: Associated with secondary membranous nephropathy. Their role seems to be pathogenic.[22][32]


The presence of anti-PLA2R has been correlated with clinical manifestations, prognosis, and recurrence of disease in membranous nephropathy.[33][34]

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.[22] These factors are summarized as follows[22]:

  • 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.[22][23][24][35][36][37][38][39][40][41]:

  • 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.[11]

Autoimmune Etiologies

  • Systemic lupus erythematosus
  • Rheumatoid arthritis
  • Mixed connective tissue disease
  • Dermatomyositis
  • Ankylosing spondylitis
  • Systemic sclerosis
  • Myasthenia gravis
  • Bullous pemphigoid
  • Autoimmune thyroid disease
  • Sjogren’s syndrome
  • Temporal arteritis
  • Crohn’s 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.[11][42] This staging has been first described by Ehrenreich and Churg in 1963.

Stage Pathological Features
Staging of Membranous Nephropathy Based on Pathological Features
Stage I
  • Small sparsely distributed electron-dense subepithelial deposits
  • No thickening of the glomerular basement membrane (GBM)
Stage II
  • Extensive subepithelial deposits
  • Formation of GBM spikes between deposits (silver-staining segments of basement membrane between dense deposits)
  • Thickening of GBM
  • Deposits are not completely surrounded by basement membrane
Stage III
  • Incorporation of dense deposits in the basement membrane
  • Deposits completely surrounded by basement membrane
Stage IV
  • Dense Deposits incorporated in the GBM
  • Irregular marked thickening and dissolution of GBM

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.[43][44][11]

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.[44][11]

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.[45][14] 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.[45][46][47] In 2010, Polanco and colleagues showed that spontaneous remission in MGN occurs in a mean time of 14.7 +/- 11.4 months.[48]

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.[49]

In patients who are in remission, progression to ESRD is virtually nill.[11][49] In patients with persistent proteinuria, however, approximately 35% of those progress into ESRD within 10 years.[11][49] These patients are also more susceptible to other non-renal complications, such as cardiovascular disease and infections.[11][49]

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.[48] 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.[43] On the other hand, it is unlikely that patients with heavy proteinuria to experience spontaneous remission.[48]

Degree of Nephrotic-Range Proteinuria (g/24hrs) Patients With Spontaneous Remission (%)[48]
Degree of Proteinuria and Rates of Spontaneous Remission in Patients with Membranous Nephropathy
3.5 - 8

37.1

8 - 12

26

> 12

22

Adapted from Polanco N, Gutierrez E, Covarsi A, et al. Spontaneous remission of nephropatic syndrome in idiopathic membranous nephropathy. J Am Soc Nephrol. 2010; 21(4):697-704

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.[48][50] 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:

Three Main Factors for Good Prognosis

Less Proteinuria[48][51]

Female Gender[48][51]

Age < 50 Years[48]


Ever since the description of PLA2R in 2009[7], serum levels of anti-PLA2R antibodies have been implicated in clinical manifestations, prognosis, and recurrence of disease in patients with membranous nephropathy.[33][22][34] Decreasing levels also seem to correlate with resolution of disease.[34]

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.[52][53][54]


Other less significant factors that have been shown to be associated with spontaneous remission:

  • Renal insufficiency > 1.5 mg/dL[47]
  • Presence of urinary alpha-1-microglobulin or beta-2-microglobulin[47][55][56]
  • Presence of urinary IgG and IgM[55][56]
  • Presence of hypertension[57]
  • Histologic evidence of interstitial fibrosis, tubular atrophy, and segmental glomerular sclerosis.[58]
  • Persistently elevated urinary C5b-9[59]


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[60]

Management

Goals of Management[43]

  • 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.[43]

Stratification of patients based on proteinuria and renal function is important for appropriate management[61]:

Risk Classification of Patients with Membranous Nephropathy and Optimal Management
Risk Definition Management
Low Mild proteinuria < 4g/24hr and normal renal function Optimization of blood pressure to <125/75 mm Hg by ACE-I and/or ARB and close monitoring of proteinuria and renal function
Moderate > 4 to < 8 g/24hr and normal renal function despite conservative management for a period more than 6 months Start management as low risk patient. If nephrotic-range proteinuria persists beyond a 6-month observation period, start steroids and immunosuppressive therapy
High > 8/24hr with or without renal insufficiency during 6-month observation period Start management as low risk patient
If nephrotic-range proteinuria or impaired renal function continues during initial conservative management, start steroids and immunosuppressive therapy even if period of observation is less than 6 months

According to the National Kidney Foundation (NKF) Kidney Disease – Improving Global Outcomes (KDIGO)[43] 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[43]

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

Months 2, 4, and 6

  • Cyclophosphamde
    • 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"[43]

  • 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 patient’s 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[43]

If the Ponticelli regimen is contraindicated or if the patient’s 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[43]

  • 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
  • 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

Regimen 2[43]

  • 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

Maintenance Dose[43]

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[43]

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[43]:

  • Mycofenolate Mofetil (MMF)
  • Rituximab
  • Eculizumab
  • ATCH

References

  1. 1.0 1.1 1.2 Glassock RJ (2010). "The pathogenesis of idiopathic membranous nephropathy: a 50-year odyssey". Am J Kidney Dis. 56 (1): 157–67. doi:10.1053/j.ajkd.2010.01.008. PMID 20378220.
  2. JONES DB (1957). "Nephrotic glomerulonephritis". Am J Pathol. 33 (2): 313–29. PMC 1934622. PMID 13402889.
  3. MOVAT HZ, McGREGOR DD (1959). "The fine structure of the glomerulus in membranous glomerulonephritis (lipoid nephrosis) in adults". Am J Clin Pathol. 32 (2): 109–27. PMID 13670133.
  4. COONS AH, KAPLAN MH (1950). "Localization of antigen in tissue cells; improvements in a method for the detection of antigen by means of fluorescent antibody". J Exp Med. 91 (1): 1–13. PMC 2135948. PMID 15395569.
  5. FARQUHAR MG, VERNIER RL, GOOD RA (1957). "An electron microscope study of the glomerulus in nephrosis, glomerulonephritis, and lupus erythematosus". J Exp Med. 106 (5): 649–60. PMC 2136823. PMID 13475621.
  6. MELLORS RC, ORTEGA LG, HOLMAN HR (1957). "Role of gamma globulins in pathogenesis of renal lesions in systemic lupus erythematosus and chronic membranous glomerulonephritis, with an observation on the lupus erythematosus cell reaction". J Exp Med. 106 (2): 191–202. PMC 2136743. PMID 13449231.
  7. 7.0 7.1 7.2 7.3 7.4 7.5 Beck LH, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD; et al. (2009). "M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy". N Engl J Med. 361 (1): 11–21. doi:10.1056/NEJMoa0810457. PMC 2762083. PMID 19571279.
  8. 8.0 8.1 Haas M, Meehan SM, Karrison TG, Spargo BH (1997). "Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997". Am J Kidney Dis. 30 (5): 621–31. PMID 9370176.
  9. 9.0 9.1 Cattran DC (2001). "Idiopathic membranous glomerulonephritis". Kidney Int. 59 (5): 1983–94. doi:10.1046/j.1523-1755.2001.0590051983.x. PMID 11318974.
  10. Korbet SM, Genchi RM, Borok RZ, Schwartz MM (1996). "The racial prevalence of glomerular lesions in nephrotic adults". Am J Kidney Dis. 27 (5): 647–51. PMID 8629623.
  11. 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 Menon S, Valentini RP (2010). "Membranous nephropathy in children: clinical presentation and therapeutic approach". Pediatr Nephrol. 25 (8): 1419–28. doi:10.1007/s00467-009-1324-5. PMC 2887508. PMID 19908069.
  12. 12.0 12.1 Moxey-Mims MM, Stapleton FB, Feld LG (1994). "Applying decision analysis to management of adolescent idiopathic nephrotic syndrome". Pediatr Nephrol. 8 (6): 660–4. PMID 7696099.
  13. Kleinknecht C, Levy M, Gagnadoux MF, Habib R (1979). "Membranous glomerulonephritis with extra-renal disorders in children". Medicine (Baltimore). 58 (3): 219–28. PMID 449658.
  14. 14.0 14.1 14.2 Fervenza FC, Sethi S, Specks U (2008). "Idiopathic membranous nephropathy: diagnosis and treatment". Clin J Am Soc Nephrol. 3 (3): 905–19. doi:10.2215/CJN.04321007. PMID 18235148.
  15. Abe S, Amagasaki Y, Konishi K, Kato E, Iyori S, Sakaguchi H (1986). "Idiopathic membranous glomerulonephritis: aspects of geographical differences". J Clin Pathol. 39 (11): 1193–8. PMC 1140761. PMID 3793935.
  16. Cahen R, Francois B, Trolliet P, Gilly J, Parchoux B (1989). "Aetiology of membranous glomerulonephritis: a prospective study of 82 adult patients". Nephrol Dial Transplant. 4 (3): 172–80. PMID 2498774.
  17. Zeng CH, Chen HM, Wang RS, Chen Y, Zhang SH, Liu L; et al. (2008). "Etiology and clinical characteristics of membranous nephropathy in Chinese patients". Am J Kidney Dis. 52 (4): 691–8. doi:10.1053/j.ajkd.2008.06.006. PMID 18805348.
  18. Lefaucheur C, Stengel B, Nochy D, Martel P, Hill GS, Jacquot C; et al. (2006). "Membranous nephropathy and cancer: Epidemiologic evidence and determinants of high-risk cancer association". Kidney Int. 70 (8): 1510–7. doi:10.1038/sj.ki.5001790. PMID 16941021.
  19. Gluck MC, Gallo G, Lowenstein J, Baldwin DS (1973). "Membranous glomerulonephritis. Evolution of clinical and pathologic features". Ann Intern Med. 78 (1): 1–12. PMID 4565900.
  20. Lee BH, Cho HY, Kang HG, Ha IS, Cheong HI, Moon KC; et al. (2006). "Idiopathic membranous nephropathy in children". Pediatr Nephrol. 21 (11): 1707–15. doi:10.1007/s00467-006-0246-8. PMID 16951933.
  21. Makker SP, Tramontano A (2011). "Idiopathic membranous nephropathy: an autoimmune disease". Semin Nephrol. 31 (4): 333–40. doi:10.1016/j.semnephrol.2011.06.004. PMC 3156416. PMID 21839366.
  22. 22.0 22.1 22.2 22.3 22.4 22.5 22.6 Glassock RJ (2012). "The pathogenesis of membranous nephropathy: evolution and revolution". Curr Opin Nephrol Hypertens. 21 (3): 235–42. doi:10.1097/MNH.0b013e3283522ea8. PMID 22388552.
  23. 23.0 23.1 Glassock RJ (2009). "Human idiopathic membranous nephropathy--a mystery solved?". N Engl J Med. 361 (1): 81–3. doi:10.1056/NEJMe0903343. PMID 19571287.
  24. 24.0 24.1 Ronco P, Debiec H (2010). "Antigen identification in membranous nephropathy moves toward targeted monitoring and new therapy". J Am Soc Nephrol. 21 (4): 564–9. doi:10.1681/ASN.2009121220. PMID 20185638.
  25. Ronco P, Debiec H (2010). "Membranous glomerulopathy: the evolving story". Curr Opin Nephrol Hypertens. 19 (3): 254–9. doi:10.1097/MNH.0b013e328336eafd. PMID 20110811.
  26. 26.0 26.1 Hofstra JM, Debiec H, Short CD, Pellé T, Kleta R, Mathieson PW; et al. (2012). "Antiphospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy". J Am Soc Nephrol. 23 (10): 1735–43. doi:10.1681/ASN.2012030242. PMC 3458465. PMID 22956816.
  27. 27.0 27.1 Lambeau G, Lazdunski M (1999). "Receptors for a growing family of secreted phospholipases A2". Trends Pharmacol Sci. 20 (4): 162–70. PMID 10322502.
  28. Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L; et al. (2011). "Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy". N Engl J Med. 364 (7): 616–26. doi:10.1056/NEJMoa1009742. PMID 21323541.
  29. 29.0 29.1 Cybulsky AV, Quigg RJ, Salant DJ (2005). "Experimental membranous nephropathy redux". Am J Physiol Renal Physiol. 289 (4): F660–71. doi:10.1152/ajprenal.00437.2004. PMC 1325222. PMID 16159900.
  30. 30.0 30.1 Penny MJ, Boyd RA, Hall BM (1998). "Permanent CD8(+) T cell depletion prevents proteinuria in active Heymann nephritis". J Exp Med. 188 (10): 1775–84. PMC 2212409. PMID 9815255.
  31. Kuroki A, Iyoda M, Shibata T, Sugisaki T (2005). "Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy". Kidney Int. 68 (1): 302–10. doi:10.1111/j.1523-1755.2005.00415.x. PMID 15954921.
  32. 32.0 32.1 van der Zee JS, van Swieten P, Aalberse RC (1986). "Serologic aspects of IgG4 antibodies. II. IgG4 antibodies form small, nonprecipitating immune complexes due to functional monovalency". J Immunol. 137 (11): 3566–71. PMID 3782791.
  33. 33.0 33.1 Hofstra JM, Beck LH, Beck DM, Wetzels JF, Salant DJ (2011). "Anti-phospholipase A₂ receptor antibodies correlate with clinical status in idiopathic membranous nephropathy". Clin J Am Soc Nephrol. 6 (6): 1286–91. doi:10.2215/CJN.07210810. PMC 3109923. PMID 21474589.
  34. 34.0 34.1 34.2 Beck LH, Fervenza FC, Beck DM, Bonegio RG, Malik FA, Erickson SB; et al. (2011). "Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy". J Am Soc Nephrol. 22 (8): 1543–50. doi:10.1681/ASN.2010111125. PMC 3148709. PMID 21784898.
  35. Debiec H, Guigonis V, Mougenot B, Decobert F, Haymann JP, Bensman A; et al. (2002). "Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies". N Engl J Med. 346 (26): 2053–60. doi:10.1056/NEJMoa012895. PMID 12087141.
  36. Prunotto M, Carnevali ML, Candiano G, Murtas C, Bruschi M, Corradini E; et al. (2010). "Autoimmunity in membranous nephropathy targets aldose reductase and SOD2". J Am Soc Nephrol. 21 (3): 507–19. doi:10.1681/ASN.2008121259. PMC 2831859. PMID 20150532.
  37. Bruschi M, Carnevali ML, Murtas C, Candiano G, Petretto A, Prunotto M; et al. (2011). "Direct characterization of target podocyte antigens and auto-antibodies in human membranous glomerulonephritis: Alfa-enolase and borderline antigens". J Proteomics. 74 (10): 2008–17. doi:10.1016/j.jprot.2011.05.021. PMID 21640210.
  38. Gitlits VM, Toh BH, Sentry JW (2001). "Disease association, origin, and clinical relevance of autoantibodies to the glycolytic enzyme enolase". J Investig Med. 49 (2): 138–45. PMID 11288754.
  39. Wakui H, Imai H, Komatsuda A, Miura AB (1999). "Circulating antibodies against alpha-enolase in patients with primary membranous nephropathy (MN)". Clin Exp Immunol. 118 (3): 445–50. PMC 1905442. PMID 10594566.
  40. Strauss J, Pardo V, Koss MN, Griswold W, McIntosh RM (1975). "Nephropathy associated with sickle cell anemia: an autologous immune complex nephritis. I. Studies on nature of glomerular-bound antibody and antigen identification in a patient with sickle cell disease and immune deposit glomerulonephritis". Am J Med. 58 (3): 382–7. PMID 46705.
  41. Debiec H, Lefeu F, Kemper MJ, Niaudet P, Deschênes G, Remuzzi G; et al. (2011). "Early-childhood membranous nephropathy due to cationic bovine serum albumin". N Engl J Med. 364 (22): 2101–10. doi:10.1056/NEJMoa1013792. PMID 21631322.
  42. Churg J, Ehrenreich T (1973). "Membranous nephropathy". Perspect Nephrol Hypertens. 1 Pt 1: 443–8. PMID 4536436.
  43. 43.00 43.01 43.02 43.03 43.04 43.05 43.06 43.07 43.08 43.09 43.10 43.11 43.12 Radhakrishnan J, Cattran DC (2012). "The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines--application to the individual patient". Kidney Int. 82 (8): 840–56. doi:10.1038/ki.2012.280. PMID 22895519.
  44. 44.0 44.1 Jennette JC, Iskandar SS, Dalldorf FG (1983). "Pathologic differentiation between lupus and nonlupus membranous glomerulopathy". Kidney Int. 24 (3): 377–85. PMID 6358633.
  45. 45.0 45.1 Zucchelli P, Ponticelli C, Cagnoli L, Passerini P (1987). "Long-term outcome of idiopathic membranous nephropathy with nephrotic syndrome". Nephrol Dial Transplant. 2 (2): 73–8. PMID 3112653.
  46. Donadio JV, Torres VE, Velosa JA, Wagoner RD, Holley KE, Okamura M; et al. (1988). "Idiopathic membranous nephropathy: the natural history of untreated patients". Kidney Int. 33 (3): 708–15. PMID 3367560.
  47. 47.0 47.1 47.2 du Buf-Vereijken PW, Branten AJ, Wetzels JF (2005). "Idiopathic membranous nephropathy: outline and rationale of a treatment strategy". Am J Kidney Dis. 46 (6): 1012–29. doi:10.1053/j.ajkd.2005.08.020. PMID 16310567.
  48. 48.0 48.1 48.2 48.3 48.4 48.5 48.6 48.7 Polanco N, Gutiérrez E, Covarsí A, Ariza F, Carreño A, Vigil A; et al. (2010). "Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy". J Am Soc Nephrol. 21 (4): 697–704. doi:10.1681/ASN.2009080861. PMC 2844306. PMID 20110379.
  49. 49.0 49.1 49.2 49.3 Beck L, Bomback AS, Choi MJ, Holzman LB, Langford C, Mariani LH; et al. (2013). "KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis". Am J Kidney Dis. 62 (3): 403–41. doi:10.1053/j.ajkd.2013.06.002. PMID 23871408.
  50. Cattran DC, Pei Y, Greenwood CM, Ponticelli C, Passerini P, Honkanen E (1997). "Validation of a predictive model of idiopathic membranous nephropathy: its clinical and research implications". Kidney Int. 51 (3): 901–7. PMID 9067928.
  51. 51.0 51.1 Laluck BJ, Cattran DC (1999). "Prognosis after a complete remission in adult patients with idiopathic membranous nephropathy". Am J Kidney Dis. 33 (6): 1026–32. doi:10.1016/S0272-6386(99)70138-1. PMID 10352189.
  52. Wehrmann M, Bohle A, Bogenschütz O, Eissele R, Freislederer A, Ohlschlegel C; et al. (1989). "Long-term prognosis of chronic idiopathic membranous glomerulonephritis. An analysis of 334 cases with particular regard to tubulo-interstitial changes". Clin Nephrol. 31 (2): 67–76. PMID 2920470.
  53. Wakai S, Magil AB (1992). "Focal glomerulosclerosis in idiopathic membranous glomerulonephritis". Kidney Int. 41 (2): 428–34. PMID 1552716.
  54. Yoshimoto K, Yokoyama H, Wada T, Furuichi K, Sakai N, Iwata Y; et al. (2004). "Pathologic findings of initial biopsies reflect the outcomes of membranous nephropathy". Kidney Int. 65 (1): 148–53. doi:10.1111/j.1523-1755.2004.00403.x. PMID 14675045.
  55. 55.0 55.1 Reichert LJ, Koene RA, Wetzels JF (1995). "Urinary excretion of beta 2-microglobulin predicts renal outcome in patients with idiopathic membranous nephropathy". J Am Soc Nephrol. 6 (6): 1666–9. PMID 8749696.
  56. 56.0 56.1 Branten AJ, du Buf-Vereijken PW, Klasen IS, Bosch FH, Feith GW, Hollander DA; et al. (2005). "Urinary excretion of beta2-microglobulin and IgG predict prognosis in idiopathic membranous nephropathy: a validation study". J Am Soc Nephrol. 16 (1): 169–74. doi:10.1681/ASN.2004040287. PMID 15563570.
  57. Scheidat S, Stahl RA (2003). "[Membranous glomerulonephritis]". Internist (Berl). 44 (9): 1120–30. doi:10.1007/s00108-003-1022-5. PMID 14566465.
  58. Ponticelli C (2007). "Membranous nephropathy". J Nephrol. 20 (3): 268–87. PMID 17557260.
  59. Schulze M, Donadio JV, Pruchno CJ, Baker PJ, Johnson RJ, Stahl RA; et al. (1991). "Elevated urinary excretion of the C5b-9 complex in membranous nephropathy". Kidney Int. 40 (3): 533–8. PMID 1787650.
  60. Glassock RJ (2010). "Idiopathic membranous nephropathy: getting better by itself". J Am Soc Nephrol. 21 (4): 551–2. doi:10.1681/ASN.2010020185. PMID 20299357.
  61. Cattran D (2005). "Management of membranous nephropathy: when and what for treatment". J Am Soc Nephrol. 16 (5): 1188–94. doi:10.1681/ASN.2005010028. PMID 15800117.

Linked-in.jpg