Membranous glomerulonephritis

Classification according to ICD-10
N04.2	Nephrotic syndrome, diffuse membranous glomerulonephritis
N06.2	Isolated proteinuria with indication of morphological changes, diffuse membranous glomerulonephritis
ICD-10 online (WHO version 2019)

The membranous glomerulonephritis (membranous glomerulopathy, epimembranous glomerulonephritis, membranous nephropathy) is a chronic inflammatory disease of the kidney corpuscles . Antibodies against proteins of the podocytes , a layer of cells in the kidney body on the filtration membrane ( glomerular basement membrane ), are believed to be the cause .

In adulthood, membranous glomerulonephritis is the most common cause of nephrotic syndrome , which is associated with high protein losses through the urine, water retention and disorders in the metabolism of blood lipids . The diagnosis is made by kidney puncture and tissue and electron microscopic examination of the kidney tissue obtained. It is characterized by the deposition of complexes of antibodies and antigen ( immune complexes ) on the outside of the glomerular basement membrane.

The course of membranous glomerulonephritis is very variable, approx. A third of the cases heals spontaneously, approx. A third remains stable and approx. A third leads to chronic kidney failure .

The treatment is carried out with drugs that inhibit the immune system ( immunosuppressive therapy ): cortisone , cyclophosphamide , chlorambucil , cyclosporine and mycophenolate mofetil .

Epidemiology

In old kidney biopsy statistics , membranous glomerulonephritis was the most common diagnosis in adult patients with proteinuria and nephrotic syndrome . The relative proportion of membranous glomerulonephritis in kidney biopsies has continuously decreased in recent years. Possibly this is due to an increase in cases of focal segmental sclerosing glomerulonephritis .

The membranous glomerulonephritis occurs in all ethnic groups and in both sexes. The idiopathic (cause unknown =) membranous glomerulonephritis is more common, however, in men over 40 years and Caucasians. In younger women, membranous glomerulonephritis should be thought of as lupus nephritis . In children, the membranous glomerulonephritis is often rare and with a hepatitis B associated.

pathology

Changes in the kidney corpuscle in membranous glomerulonephritis visible under the electron microscope
Black - Immune complexes
dark violet - Basement membrane
pink - Endothelium
green - Visceral epithelium
light violet - Mesangium

In the light microscopy by a diffuse thickening of the place glomerular basement membrane in all renal (glomeruli) . The number of cells in the kidney corpuscles is not increased. In the early stages the glomeruli can appear inconspicuous, in more advanced stages there are fine holes in the basement membrane, on the outside (= the subepithelial side) of the basement membrane, fine protrusions, so-called "spikes", form. Occasionally, subepithelial protein deposits can be detected in the trichrome stain . As the disease progresses, scarring (sclerosis) of the kidney corpuscles and changes in the kidney tubules and interstitial tissue (interstitium) of the kidney occur.

In fluorescence microscopy , fine granular deposits of IgG and C3 are found along the basement membrane.

The electron microscopy shows electron-dense deposits ( deposits ) on the outer side (the subepithelial) side of the basement membrane, a fusion of the foot processes overlying the glomerular cover cells (podocytes) and a broadening of the basement membrane by deposition of newly formed extracellular matrix between the immune deposits, the "spikes" . In the course of the disease, the immune depots are finally completely enclosed by the basement membrane.

The degree of changes in the basement membrane enables histological (tissue-like) staging, but this does not correlate with the severity of the disease or the response to medication .

• Stage I: Isolated small deposits (immune depots) without thickening of the basement membrane.
• Stage II: More extensive immune depots with basement membrane extensions (spikes) between the depots and thickening of the basement membrane.
• Stage III: The immune depots are completely surrounded by basement membrane (intramembranous immune depots), the basement membrane is thickened.
• Stage IV: Irregular thickening of the basement membrane with immune depots within the membrane. 

Pathogenesis

On the basis of findings made on experimental models, it is assumed that the immune depots are formed instead of the deposits (“in situ”). To do IgG antibodies to basement membrane happen and antigens bind either at the foot processes or in the vicinity expressed are or from the blood stream have reached the outside of the basement membrane.

Animal model Heymann nephritis (Megalin)

As early as 1959 Heymann succeeded in producing membranous glomerulonephritis in rats by inoculating the animals with an extract of kidney tubule cells in Freund's adjuvant . In the meantime, megalin and cubilin have been identified as target antigens , which are expressed in membrane invaginations of tubular and glomerular epithelial cells, the clathrin coated pits , and are responsible for the endocytosis of many substances in several tissue types.

The formation of immune complexes on the outside of the basement membrane leads to complement activation . This damages the podocytes. A disruption of the cytoskeleton leads to the loss of the integrity of the glomerular slit membrane. This in turn leads to the transfer of protein into the urine, to proteinuria . In addition, there is an overproduction of components of the basement membrane, collagen IV and laminin , and thus widening of the basement membrane.

In humans, the antigen responsible for membranous nephritis was not known for a long time - megalin is not expressed in the human glomerulus.

Antenatal membranous glomerulonephritis (neutral endopeptidase)

Observations of antenatal membranous nephritis suggested a similar pathomechanism in humans: in the human glomerulus, the podocytes express the enzyme neutral endopeptidase . Missing the mother due to a mutation of this enzyme, it may be during the first pregnancy to immunization are the mother if the fetus this enzyme expressed in the kidney. In a second pregnancy, maternal antibodies against neutral endopeptidase can cross the placenta and cause membranous glomerulonephritis with nephrotic syndrome in the fetus . A few months after birth , the maternal antibodies disappear from the child's blood, the immune depots in the kidneys dissolve, and the nephrotic syndrome heals spontaneously.

Idiopathic membranous glomerulonephritis (phospholipase A ₂ receptor type M; THSD7A)

In 2009, Beck et al. In the serum of 70% of patients with idiopathic membranous glomerulonephritis an antibody of the IgG4 type , which reacts with a certain protein from the extract of kidney corpuscles. The protein was identified as a phospholipase A₂ receptor type M (PLA ₂ R). This receptor protein in normal human glomeruli on the surface of the podocytes expressed and can be detected in patients with membranous glomerulonephritis in the immune depots. In contrast , the antigen PLA ₂ R cannot be detected in the serum . This is a strong indication that in membranous glomerulonephritis the immune complexes are formed directly on the podocytes and not initially in the serum with subsequent deposition on the outside of the glomerular basement membrane. Commercial tests for the phospholipase A2 receptor antibody are now widely available. Since the antibody titer correlates with the disease activity, it can be used for therapy decision-making and therapy monitoring. In addition to the PLA2 receptor AK, an antibody against the thrombospondin type 1 domain 7A (THSD7A) has now been identified for which there are no widespread commercial tests.

Early childhood membranous glomerulonephritis (bovine serum albumin)

In children between the ages of 5 months and 2.3 years with membranous nephropathy, high concentrations of bovine serum albumin and antibodies of the type IgG1 and IgG4 were found in the blood . Together with bovine serum albumin, these antibodies could also be detected in the epimembranous deposits of the kidney corpuscles . IgG1 and IgG4, which reacted with bovine serum albumin, were also found in the eluate from kidney biopsies. It is believed that small amounts of bovine serum albumin from cow's milk can be absorbed in the intestine in undigested or partially digested form. Antibodies against bovine serum albumin can be found in the blood of almost all small children. In the children with membranous nephropathy, the serum levels of bovine serum albumin were higher than in healthy controls and the bovine serum albumin was in a cationic (positively charged) form. All children treated with prednisone , mycophenolate mofetil, or cyclosporine had partial or complete remission .

Secondary membranous glomerulonephritis

In cases where the membranous Glomerulonephtritis result was another disease-specific antigens could be detected in immune deposits: double stranded - DNA at erythematosus lupus , thyroglobulin for thyroiditis , hepatitis B antigen, Treponema antigen and Helicobacter pylori antigen in the corresponding Infections , as well as carcinoembryonic antigen and prostate-specific antigen in tumor diseases .

In the tissue examination, the following findings indicate a secondary genesis of membranous glomerulonephritis:

• Cell proliferation in the mesangium and capillary tangles (mesangial and endicapillary proliferation )
• Immunohistological detection of all immunoglobulin classes and complement component C1q .
• Detection of immunoglobulins other than IgG4 .
• Immune depots on the inside of the basement membrane (subendothelial immune depots), in the mesangium, along the basement membranes of the renal tubules (tubular basement membranes) or in vessel walls.
• Electron microscopically detectable tubular or reticulated (tubuloreticular) inclusions in the endothelial cells of the capillary ball of the kidney corpuscles.

The role of T cells

In addition to antibodies, T helper cells are also involved in the pathogenesis of glomerulonephritis.

Th1 helper cells predominate in glomerulonephritis that is associated with increased cell growth, such as the rapidly progressive glomerulonephritis . In membranous glomerulonephritis, on the other hand, as in minimal change glomerulonephritis , Th2 helper cells predominate .

genetics

A genome-wide association study in 556 patients of European origin revealed an association with two single nucleotide polymorphisms . On chromosome 2q24 there was an association with the gene for the phospholipase A₂ receptor type M (PLA ₂ R1) . However, the closest association was to an allele on chromosome 6p21 , which codes for an HLA class II antigen (HLA-DQA1) . This allele may facilitate an autoimmune reaction against the body's own antigens, such as variants of the PLA ₂ R1.

etiology

In about 75% of cases of membranous glomerulonephritis, no cause is found ( idiopathic membranous glomerulonephritis ).

The following speak in favor of secondary membranous glomerulonephritis caused by another disease:

• Tubuloreticular structures in the podocytes, which are caused by interferon alpha , suggest lupus erythematosus (Fig. Below ).
• Immune depots on the inside of the glomerular basement membrane (subendothelial depots) or in the mesangium (tissue between the kidney corpuscles) speak for the presence of circulating immune complexes in the blood (e.g. in post-infectious glomerulonephritis ) and against the in situ formation of immune depots .
• Immune deposits on the basement membranes of the renal tubules are rare in idiopathic membranous nephritis, but common in secondary forms.
• In idiopathic membranous nephritis, immunoglobulin G of the isotype IgG4 is predominantly found in the immune depots , in lupus erythematosus IgG2, IgG3, IgA , IgM and complement factor C1q , in tumors IgG1 and IgG2 predominate.

The causes of secondary membranous glomerulonephritis are diverse:

• A membranous nephritis is found in about 10–20% of cases of kidney involvement in lupus erythematosus . Kidney disease can precede the manifestation of lupus erythematosus, so this diagnosis should always be considered, especially in young women with membranous nephritis.
• Drugs such as gold salts , penicillamine , bucillamine , nonsteroidal anti-inflammatory drugs , mercaptopropionylglycine , high-dose captopril , and monoclonal antibodies such as etanercept , infliximab and adalimumab can lead to membranous nephritis.
• In endemic areas , membranous nephritis can occur in chronic carriers of the hepatitis B virus, especially in children. Mainly HBe antigen and anti-HBe antibodies are detectable in the immune depots. In children, membranous nephritis often heals in hepatitis B, but in adults there is often a chronic loss of kidney function . Membranous nephritis has also been described in carriers of the hepatitis C virus.
• About 5–20% of adults with membranous nephritis, especially those over 65 years of age, have a tumor disease , often tumors of the lungs and gastrointestinal tract , less often malignant diseases of the blood-forming system .
• Membranous nephritis has also been described as a result of kidney or stem cell transplantation .
• Rare causes of membranous nephritis are schistosomiasis , malaria quartan , syphilis , sarcoidosis , Sjogren's syndrome and chronic formaldehyde - exposure .
• Mercury compounds that z. Used in traditional Chinese medicine or skin whitening creams, for example, can also lead to membranous nephritis.

Membranous glomerulonephritis and other kidney diseases

Membranous glomerulonephritis has also been reported along with other glomerular kidney diseases.

• Focal-segmental glomerulosclerosis : The sclerotic (scarred) changes in the kidney corpuscle may be the result of membranous nephritis or increased intraglomerular pressure. Sclerotic lesions in the kidney biopsy indicate a progressive deterioration in kidney function and thus a poor prognosis .
• Diabetic nephropathy : The immune depots may contain pig insulin and antibodies against pig insulin. An improvement in the nephrotic syndrome after switching to human (human) insulin has been described.
• Rapidly progressive glomerulonephritis : In about 5% of cases, membranous nephritis can be superimposed by rapidly progressive glomerulonephritis.
• Occasionally, the histological changes of membranous glomerulonephritis occur together with IgA nephropathy , Goodpasture syndrome, or Wegener's granulomatosis .

clinic

About 80% of the patients have a nephrotic syndrome with possibly considerable water retention in the tissues, swelling of the legs and eyelids, weight gain and a decrease in urine output. About 20% of those affected have a lesser degree of proteinuria without additional symptoms . In urine sediment oval fat bodies, fat droplets and fat cylinders are frequently encountered. Microhematuria is present in around 50% of patients, i.e. red blood cells (erythrocytes) are detected in the urine . The albuminuria leads to disruption of tubular transport, in the urine is therefore often glucose despite normal blood glucose values detectable ( glucosuria ).

The blood test usually reveals a decrease in albumin and a severe increase in blood lipids (hyperlipidemia)

About 70% of patients have normal blood pressure and kidney function at the onset of the disease . An acute renal failure is rare; Causes are hypovolaemia due to aggressive treatment with water tablets (diuretics) , rapidly progressive glomerulonephritis or the occlusion of the renal vein by a blood clot ( renal vein thrombosis ).

diagnosis

Kidney biopsy

The diagnosis of membranous glomerulonephritis can only be made through a kidney biopsy. A kidney biopsy should be done in all adults with nephrotic syndrome of unknown origin. Children with nephrotic syndrome usually have minimal change glomerulonephritis that responds well to glucocorticoids , so that children do not need a kidney biopsy for the time being.

Laboratory diagnostics

The following laboratory tests should be performed to identify a possible secondary cause of membranous glomerulonephritis:

• Antinuclear Antibody . A high titer indicates the presence of systemic lupus erythematosus .
• Complement factor C3 . A reduction in the complement factor C3 is in systemic lupus erythematosus and hepatitis B found. In idiopathic membranous glomerulonephritis, the C3 level is normal.
• Serological markers of hepatitis B and hepatitis C.

Tumor diagnostics

Some patients with membranous glomerulonephritis have a tumor . In most cases, the cancer is known by the time the membranous nephropathy manifests. In rare cases, kidney disease manifests itself before tumor disease.

The recommended cancer screening examinations should always be carried out. At increased risk for lung cancer one should x-ray examination , if necessary, a computed tomography of the thorax done. A further search for a tumor is only recommended if there is additional evidence of cancer, such as evidence of occult blood in the stool , anemia or unexplained weight loss.

Course of the disease and prognosis

Without treatment, the disease has a relatively favorable spontaneous course:

• In about a third of the patients, the proteinuria normalizes (complete remission ) within a year .
• In 25–40% of cases, the proteinuria falls below 2 g per day (partial remission).
• However, after 5 years around 14% of those affected suffered a complete loss of kidney function ( end-stage renal failure ), after 10 years in 35% and after 15 years in 41% of those affected.

Treatment with drugs that inhibit the renin-angiotensin-aldosterone system improves the prognosis.

Risk factors for an unfavorable course of the disease

In view of the often favorable course of the disease and the potentially serious side effects of treatment, immunosuppressive therapy should only be started in patients who have severe nephrotic syndrome or a high risk of progressive deterioration in kidney function.

• In contrast to other glomerular disorders, there is no relationship between the extent of tubulointerstitial damage and response to treatment or the rate of renal loss.
• There is an increased risk of progression in:
  • Men over 50 years of age with proteinuria over 8 g / day for over 6 months. Even with very high protein excretion, however, remissions are observed in approx. 20% of the cases.
  • Patients with elevated creatinine at diagnosis.
• Asians have a better prognosis than people from other ethnic groups .
• Women, children, young adults, patients with non-nephrotic proteinuria (protein excretion <3.5 g / day) and normal kidney function three years after the onset of the disease have a favorable prognosis.
• Patients with drug-induced membranous nephritis also have a good prognosis. The proteinuria can increase up to a year after discontinuation of the triggering drug and it can take up to three years for the protein excretion to normalize.

Complications

If there is an acute loss of kidney function in the course of the disease , this is usually due to the following complications:

• acute renal vein thrombosis (occlusion of the renal vein with a blood clot), sometimes characterized by flank pain
• drug-induced interstitial nephritis with leukocytes , particularly eosinophils in urine
• rapid progressive glomerulonephritis with red blood cells and red cell casts in the urine.

therapy

General therapeutic measures

The general goals of the treatment of membranous nephropathy are:

• Control of water retention (edema) with water tablets (diuretics) ,
• Ensuring adequate food intake,
• Reduction of proteinuria and control of high blood pressure with ACE inhibitors and AT1 antagonists ,
• Correction of the often pronounced fat metabolism disorder (hyperlipidaemia) by statins , as well
• Prevention of thromboembolic complications through the administration of anticoagulant substances if the serum albumin level has fallen below 2 g / dl due to protein losses in the urine.

Immunosuppressive Therapy

Due to the favorable prognosis of the disease with a high proportion of spontaneous remissions and the potentially serious side effects of immunosuppressive treatment , this is only started if there is evidence of an unfavorable prognosis after the course of the disease has been observed over a longer period of time using general therapeutic measures.

• Patients without symptoms, with proteinuria below 3.5 g / day, are generally not treated with immunosuppressants because the long-term prognosis is favorable. However, regular checks of kidney function and proteinuria are necessary in order to detect disease progression in good time.
• Patients with proteinuria above 3.5 g / day who are symptomatic or whose water retention (edema) can be easily controlled with diuretics should be observed over a long period of time prior to immunosuppressive therapy. In up to 65% of those affected, general therapeutic measures can lead to spontaneous remission of the disease, especially in women, children and young adults with normal kidney function and a prognostically favorable tissue finding.
• Immunosuppressive therapy is started in patients with a poor prognosis:
  • at not by a lack of volume declared renal impairment and adverse prognostic histological findings, particularly scarring (fibrosis) of glomeruli (glomeruli) and interstitial tissue (interstitial) of the kidney ,
  • in severe symptomatic nephrotic syndrome with pronounced water retention (edema) , severe lipid metabolism disorder (hyperlipidemia) and proteinuria over 10 g / day,
  • if there are indications in the follow-up of an increasing renal impairment,
  • in men over 50 years of age with persistent nephrotic syndrome,
  • when thrombosis and / or embolism occur as a complication of nephrotic syndrome.

Different immunosuppressive drugs are used:

• The alkylating substances cyclophosphamide and chlorambucil are mostly used in combination with prednisone . This combination appears to be the most effective form of treatment. However, serious side effects such as urinary bladder inflammation and long-term effects such as infertility and an increased risk of cancer are possible.
• A monotherapy with cortisone is less stressful, but the response rates are low.
• If treatment with alkylating agents does not respond , or if the person concerned does not want this because of the possible side effects, treatment can be carried out with cyclosporine , possibly in combination with prednisone .
• The monoclonal antibody rituximab , which is selectively directed against B cells , reduces proteinuria. In an Italian study, ten out of fifty patients had a complete remission of the disease. Kidney biopsies from seven of these ten patients showed complete or extensive regression of the immune depots. Comparative studies with ACE inhibitors / AT1 antagonists and long-term observations are still lacking. A rare and serious side effect of rituximab is progressive multifocal leukoencephalopathy .
• The optimal duration of immunosuppressive treatment is unknown.

Alternative treatments

A variety of alternative substances have been used in patients who have not responded to conventional therapies:

• Treatment with mycophenolate mofetil for 12 months did not improve the proteinuria and was associated with severe side effects.
• Azathioprine may not have any effect on disease progression, but serious side effects have been reported.
• After intravenous administration of immunoglobulin , an improvement in proteinuria has been described in individual case reports.
• In patients who could not tolerate cyclosporine , tacrolimus was used as an alternative ; no comparative studies have yet been carried out.
• In a pilot study, pentoxifylline led to an improvement in proteinuria; larger studies have so far been lacking.
• Nonsteroidal anti-inflammatory drugs also lower proteinuria. However, since these substances can damage the kidneys, they are usually not used.
• In uncontrolled studies, adrenocorticotropin reduced proteinuria; data on the long-term course have not yet been presented.

Web links

• Epimembranous Glomerulonephritis Pathology - Pathopic image database of the University of Basel ( PathoPic - Instructions ; PDF; 2.2 MB)
• Agnes Fogo et al .: Membranous Glomerulonephritis . Atlas of Renal Pathology. In: Am J Kidney Dis , 31 (3), 1998, p. E1
• S. Krautzig: Case report with images . 48-year-old surgeon with edema. In: Clinical Nephrology , June 8, 2007, Hannover Medical School

Individual evidence

1. ↑ ^{a b c} Fernando C. Fervenza et al .: Idiopathic Membranous Nephropathy: Diagnosis and Treatment . In: Clin J Am Soc Nephrol . No. 3 , 2008, p. 905-919 ( Article ).
2. ^ Peggy WG et al .: Idiopathic Membranous Nephropathy: Outline and Rationale of a Treatment Strategy . In: American Journal of Kidney Diseases . No. 46 , 2005, pp. 1012-1029 ( Article ).
3. ↑ staging of pathopic
4. ↑ Motoyoshi Y, Matsusaka T, Saito et al .: Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria . In: Kidney Int . 74, No. 10, November 2008, pp. 1262-9. doi : 10.1038 / ki.2008.405 . PMID 18769366 .
5. ^ Baines RJ, Brunskill NJ: The molecular interactions between filtered proteins and proximal tubular cells in proteinuria . In: Nephron Exp. Nephrol . 110, No. 2, 2008, pp. E67–71. doi : 10.1159 / 000161982 . PMID 18849618 .
6. ↑ Farquhar, MG: The Heymann nephritis antigenic complex megalin (gp330) and RAP . In: J Am Soc Nephrol . No. 6 , 1995, pp. 35-47 ( Article ).
7. ↑ Laurence H Beck, Ramon GB Bonegio, Gérard Lambeau, David M Beck, David W Powell, Timothy D Cummins, Jon B Klein, David J Salant: M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy . In: The New England Journal of Medicine . 361, No. 1, July 2, 2009, ISSN  1533-4406 , pp. 11-21. doi : 10.1056 / NEJMoa0810457 . PMID 19571279 .
8. ^ To S. De Vriese, Richard J. Glassock, Karl A. Nath, Sanjeev Sethi, Fernando C. Fervenza: A Proposal for a Serology-Based Approach to Membranous Nephropathy. J Am Soc Nephrol. 2017 Feb; 28 (2): 421-430 doi: 10.1681 / ASN.2016070776
9. ↑ Hanna Debiec, Florence Lefeu, Markus J. Kemper, Patrick Niaudet, Georges Deschênes, Giuseppe Remuzzi, Tim Ulinski, Pierre Ronco: Early-childhood membranous nephropathy due to cationic bovine serum albumin . In: The New England Journal of Medicine . 364, No. 22, June 2, 2011, ISSN  1533-4406 , pp. 2101-2110. doi : 10.1056 / NEJMoa1013792 . PMID 21631322 .
10. ↑ Horia C Stanescu, et al .: Risk HLA-DQA1 and PLA (2) R1 alleles in idiopathic membranous nephropathy . In: The New England Journal of Medicine . 364, No. 7, February 17, 2011, ISSN  1533-4406 , pp. 616-626. doi : 10.1056 / NEJMoa1009742 . PMID 21323541 .
11. ↑ Katharina Glatz-Krieger, Dieter Glatz-Krieger: Glomerulonephritis in Lupus erythematosus . In: PathoPic Pathologie image database of the University of Basel . 2002 ( article ).
12. ↑ Shi-Jun Li, et al .: Mercury-induced membranous nephropathy: clinical and pathological features . In: Clinical Journal of the American Society of Nephrology . 5, No. 3, March 2010, ISSN  1555-905X , pp. 439-444. doi : 10.2215 / CJN.07571009 . PMID 20089494 .
13. ↑ ^{a b c} Natalia Polanco, et al .: Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy . In: Journal of the American Society of Nephrology: JASN . 21, No. 4, April 2010, ISSN  1533-3450 , pp. 697-704. doi : 10.1681 / ASN.2009080861 . PMID 20110379 .
14. ↑ Michelle A Hladunewich, Stephan Troyanov, Jennifer Calafati, Daniel C Cattran: The natural history of the non-nephrotic membranous nephropathy patient . In: Clinical Journal of the American Society of Nephrology: CJASN . 4, No. 9, September 2009, ISSN  1555-905X , pp. 1417-1422. doi : 10.2215 / CJN.01330209 . PMID 19661220 .
15. ↑ Julia M Hofstra, et al .: Early versus late start of immunosuppressive therapy in idiopathic membranous nephropathy: a randomized controlled trial . In: Nephrology Dialysis Transplantation . 25, No. 1, January 2010, ISSN  1460-2385 , pp. 129-136. doi : 10.1093 / ndt / gfp390 . PMID 19666912 .
16. ↑ Piero Ruggenenti, Paolo Cravedi, Maria Chiara Sghirlanzoni, Elena Gagliardini, Sara Conti, Flavio Gaspari, Gianfranco Marchetti, Mauro Abbate, Giuseppe Remuzzi: Effects of rituximab on morphofunctional abnormalities of membranous glomerulopathy . In: Clinical Journal of the American Society of Nephrology: CJASN . 3, No. 6, November 2008, ISSN  1555-905X , pp. 1652-9. doi : 10.2215 / CJN.01730408 . PMID 18684896 .
17. ^ Bertrand Dussol, et al .: Mycophenolate mofetil monotherapy in membranous nephropathy: a 1-year randomized controlled trial . In: American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation . 52, No. 4, October 2008, ISSN  1523-6838 , pp. 699-705. doi : 10.1053 / j.ajkd.2008.04.013 . PMID 18585835 .

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !