Membranoproliferative glomerulonephritis

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

The term membranous glomerulonephritis was used first by Bell in 1946 to describe a category of glomerular renal disease classified within the spectrum of Ellis type II glomerulonephritis. This category also included lipoid nephrosis, lobular glomerulonephritis, and chronic glomerulonephritis. In 1957, David Jones, a renal pathologist from Syracuse University in New York, separated membranous glomerulonephritis as a distinct morphologic entity. Jones fully illustrated the special features of this lesion such as lobular glomerulonephritis, lipoid nephrosis and chronic glomerulonephritis. Thickening of the capillary wall and alteration in basement membrane structure were described. Electron-dense subepithelial locations were identified by Movat and McGregor in 1959 using electron microscopic methods. Mellors  in 1957 identified the unique lesion of membranous glomerulonephritis, the presence of immunoglobulin in the deposits, using the immunofluorescence technique. Thus, over the span of just 2 years, the triad of essential features of membranous glomerulonephritis were described. These are still the fundamental features used today to identify membranous glomerulonephritis, now called membranoproliferative glomerulonephritis MPGN.

• In 1946, Bell coined the term membranous glomerulonephritis. ^[1]

• In 1957, David Jones, a renal pathologist from Syracuse University in New York, described membranous glomerulonephritis as a distinct morphologic entity.
• Prof. Jones was the first to illustrate complete features of MPGN which include:
  • Lobular glomerulonephritis
  • Lipoid nephrosis
  • Chronic glomerulonephritis
• He also described the characteristic thickening of the capillary wall and alteration in basement membrane structure.

• In 1959, Movat and McGregor identified electron-dense subepithelial deposits using electron microscope.
• In 1957, Mellors was the first to identify immunoglobulin deposits as the third component of membranous glomerulonephritis and later described the triad of MPGN.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ali Poyan Mehr, M.D. [2] Olufunmilola Olubukola M.D.[3]

Like many forms of glomerulopathies, membranoproliferative glomerulonephritis (glomerulopathy) has been a diagnosis of tissue pathology rather the diagnosis of a specific disease entity. Therefore the term membranoploriferative glomerulonephritis (MPGN) relates to a pattern of glomerular injury which can be caused by many disease states. Historically the nephropathologists divided MPGN into 3 distinctive categories to shed light into what may be causing this type of kidney injury: MPGN type 1: mesangial and subendothelial electron dense deposits MPGN type 2: electron dense material in the glomerular basement membrane MPGN type 3: subepithelial deposits with basement membrane spikes This categorization, however is now out of date. The recognition of several new disorders as the underlying cause of MPGN, and the lack of clinical, prognostic or therapeutic relevance made this categorization less useful. For completeness and to help better accommodate the transition from old to new classification, below both classifications are reviewed. Classification of MPGN based on immunofluorescence microscopy is a result of all advances in the understanding of the pathogenesis of the disease. Based on this advanced techniques, there are three types of MPGN ^[1]:Immune-complex-mediated MPGN (Type I) ,Complement-mediated MPGN (Type II), Non-Ig/complement-mediated MPGN (Type III)

MPGN can be classified three types based on immunofluorescence microscopy techniques . ^[2];

• Immune-complex-mediated MPGN (Type I)
• Complement-mediated MPGN (Type II)
• Non-Ig/complement-mediated MPGN (Type III)

It is the most common type.

• Circulating immune complexes are present in approximately 33% .
• Immune complexes are found in the mesangium and subendothelial spaces.

• Dense deposits are observed in MPGN type II.
• Complement mediated

• They are continuous, dense ribbon along the basement membranes of the glomeruli, tubules, and Bowman’s capsule .

Type III is very rare

• It is characterized by a combination of subepithelial deposits, deposits in the mesangium and subendothelial space.
• There is complex disruption of the glomerular basement membrane with large lucent area.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2] Associate Editor(s)-in-Chief: Olufunmilola Olubukola M.D.[3],Nazia Fuad M.D.

MPGN membrano proliferative glomerulonephritis, also known as mesangiocapillary glomerulonephritis, is a glomerular injury on light microscopy that is characterized by mesangial hypercellularity, endocapillary proliferation, and double-contour formation along the glomerular capillary walls. “MPGN” includes two characteristic histologic changes:Thickened glomerular basement membrane (GBM) due to deposition of immune complexes and/or complement factors, intrusion of the mesangial cells and other cellular elements between the glomerular basement membrane and the endothelial cells, and new basement membrane formation. Mesangial and endocapillary cellularity is increased resulting in lobular appearance of the glomerular tuft. Proliferation of mesangial cells and circulating monocytes results in increased cellularity.Two mechanisms are involved in the pathogenesis of MPGN,Immune complex deposition leading to activation of complement (immune complex-mediated) and dysregulation and persistent activation of the alternative complement pathway.

• Type I MPGN:^[1][2]
  • It results from presesnce of a persistent antigen in blood.
  • This leads to generation of nephritogenic immune complexes that localize to the subendothelial spaces.
  • Innate immunity to both the generation of antibodies that are deposited as immune complexes and to the local inflammatory responses directed at the glomerular immune deposits plays a role.
  • The immune complexes activate the complement system via the classical pathway.
  • This results in the generation of chemotactic factors (C3a, C5a) that mediate the accumulation of platelets and leukocytes.
  • Activation of complements (C5b-9) directly induce cell injury.
  • Leukocytes release oxidants and proteases that result in capillary wall damage and cause proteinuria.
  • Cytokines and growth factors released by glomerular cells lead to mesangial proliferation and expansion. 

• Type II MPGN:
  • It results from the uncontrolled systemic activation of the alternative pathway of the complement cascade.
  • In most patients, loss of complement regulation is caused by the C3 nephritic factor , an immunoglobulin (Ig)G autoantibody that binds and prevents the inactivation of C3 convertase (C3bBb) of the alternative pathway.
  • This results in the breakdown of C3.
  • Another cause of type II MPGN is due to mutations in the complement regulatory protein, factor H, or to autoantibodies that impede factor H function, highlighting the role of deregulated alternative complement pathway activity in type II MPGN.

• Type III MPGN:
  • It is thought to be due to a slow-acting nephritic factor that stabilizes a properdin dependent C5-convertase, (Cb3)2BbP.
  • (Cb3)2BbP activates the terminal pathway of the complement system.
  • This nephritic factor has not been reported in healthy subjects.unnlike C3NeF.
  • In addition, the deposits present in renal biopsies of patients with type III MPGN are closely associated with the circulating nephritic factor-stabilized convertase and with hypocomplementemia suggesting that NeFt is fundamental to the pathogenesis of type III MPGN.

• Cryoglobulinemic MPGN :
  • A large percentage of patients with chronic HCV infection develop type II cryoglobulins.
  • However, only a minority of such patients with detectible cryoglobulinemia have clinical manifestations of cryoglobulinemic MPGN.
  • It is unclear why some cryoglobulins are more pathogenic than others, or why cryoglobulins deposit in the kidneys.
  • Recognition of the components of cryoprecipitates, which contain HCV core protein, by circulating leukocytes and intrinsic glomerular cells leads to the production of inflammatory mediators that characterize the glomerular injury of cryoglobulinemic MPGN.

• Glomeruli generally are enlarged and hypercellular
• There is increase in mesangial cellularity and matrix.
• Mesangial increase, when generalized throughout the glomeruli, causes an exaggeration of their lobular form.
• This give rise to the alternative name of lobular nephritis.
• Infiltrating neutrophils and monocytes contribute to glomerular hypercellularity.
• The capillary basement membranes are thickened by interposition of mesangial cells and matrix into the capillary wall.
• This gives rise to the double-contoured appearance of the capillary wall, best appreciated with the methenamine silver stain or the periodic acid-Schiff reagent.
• Crescents may be visible in 10% of patient biopsy specimens.
• Interstitial changes, including inflammation, interstitial fibrosis, and tubular atrophy, are observed in patients with progressive decline in GFR.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2] Associate Editor(s)-in-Chief: Olufunmilola Olubukola M.D.[3] Nazia Fuad M.D.

The most common causes for membranoproliferative glomerulonephritis autoimmune diseases, mainly systemic lupus erythematosus (SLE), Sjögren syndrome, rheumatoid arthritis, inherited complement deficiencies (esp C2 deficiency), scleroderma, Celiac disease .Chronic infections also play major role such as viral infections like hepatitis B, hepatitis C, and cryoglobulinemia type II, bacterial infections such as endocarditis, infected ventriculoatrial (or jugular) shunt, multiple visceral abscesses, leprosy. Protozoal – malaria, schistosomiasis. Rare causes of MPGN include non-Hodgkin lymphoma, renal cell carcinoma, snake venom, splenorenal shunt surgery for portal hypertension , melanoma, alpha-1-antitrypsin deficiency, and cryoglobulinemic glomerulonephritis and Idiopathic MPGN .

There are no life-threatening causes of membranoproliferative glomerulonephritis. , however complications resulting from untreated membranoproliferative glomerulonephritis are common.

Common causes of MPGN may include:^[1][2][3]

• Immune complex–mediated disease

• Autoimmune diseases
  • Systemic lupus erythematosus (SLE)
  • Sjögren syndrome

• • Rheumatoid arthritis
  • Scleroderma
  • Celiac disease

• Chronic infections
  • Viral – Hepatitis B, hepatitis C, and cryoglobulinemia type II
  • Bacterial – Endocarditis, infected ventriculoatrial (or jugular) shunt, multiple visceral abscesses, leprosy
  • Protozoal – Malaria, schistosomiasis
  • Other infections – Mycoplasma, Lyme Disease^[4]
• Miscellaneous – Chronic liver disease (cirrhosis and alpha1-antitrypsin deficiency)

• Chronic and recovered thrombotic microangiopathies

• Healing phase of hemolytic uremic syndrome and/or thrombotic thrombocytopenic purpura
• Syndromes of circulating antiphospholipid (anticardiolipin) antibodies
• Radiation nephritis
• Nephropathy associated with bone marrow transplantation
• Sickle cell anemia and polycythemia
• Transplant glomerulopathy

• Malignant neoplasms

• Lymphoma
• Leukemia
• Carcinoma

Less common causes of MPGN include

• Idiopathic forms of MPGN or of unknown association^[5]

• • MPGN type I
  • MPGN type II or dense deposit disease.
  • MPGN type III
• Paraprotein deposition diseases

• • Glomerulonephropathies associated with cryoglobulinemia type I
  • Waldenström macroglobulinemia
  • Immunotactoid glomerulopathy
  • Immunoglobulin light chain or heavy chain deposition diseases
  • Fibrillary glomerulonephritis
• Non-Hodgkin lymphoma
• Renal cell carcinoma
• Snake venom
• Splenorenal shunt surgery for portal hypertension
• Melanoma
• Alpha-1-antitrypsin deficiency
• Inherited complement deficiencies, specially C2 deficiency

• MPGN is caused by a mutation in the complement factor H-related protein 5 (CFHR5) gene.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2], Mehrian Jafarizade, M.D [3]

There are some differential diagnosis mentioned for MPGN as they have some symptoms and signs in shared, the most relevant diseases are acute glomerulonephritis, IgA Nephropathy, LupusNephritis, poststreptococcal glomerulonephritis, and rapidly progressive Glomerulonephritis (RPGN).

According to the pathophysiology of Membranoproliferative Glomerulonephritis (MPGN) various differential diagnosis include :^[1]

Various types of glomerular diseases should be differentiated from each other based on associations, presence of pitting edema, hematuria, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light and electron microscopic features. The above table differentiates between various types of glomerular diseases:

Some infectious diseases such as HIV, HBV, HCV, syphilis, leprosy, malaria, and schistosomiasis may cause glomerular diseases.

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Membranoproliferative glomerulonephritis (MPGN) is observed in 6-12% of US patients receiving renal biopsies. This entity accounts for 7% of children and 12% of adults with idiopathic nephrotic syndrome. MPGN causes significant proportion of the cases of nephritis among patients in nonindustrialized countries. For example, in Mexico, MPGN accounts for 40% of all patients with nephritis. Most of these patients have type I disease; MPGN type II is uncommon. However, the incidence of MPGN type I is decreasing progressively in developed countries, which may be explained by a change in environmental factors, especially a decline in infections. In an investigation of the changing patterns of adult primary glomerular disease occurrence in a single region of the United Kingdom, Hanko analyzed the results of 1844 native renal biopsies taken between 1976 and 2005 (inclusive) and found the presence of primary glomerulonephritis was revealed in 49% of the biopsies, with the most common forms being immunoglobulin A (IgA) nephropathy (38.8%). Other common forms were membranous nephropathy (29.4%), minimal-change disease (MCD) (9.8%), MPGN type 1 (9.6%), and focal segmental glomerulosclerosis (FSGS) (5.7%). The incidence of IgA nephropathy increased significantly over the study period, whereas the occurrence of membranous nephropathy decreased. In the United States, MPGN predominantly affects the white population. Type I disease affects women more often than men, whereas a nearly equal sex distribution is seen in MPGN type II. The idiopathic forms of MPGN are more common in children and young adults (range, 6-30 y). Isolated reports of involvement in patients as young as 2 years and as old as 80 years are noted in the literature. Secondary types of MPGN predominate among adults. By dividing glomerular diseases into two subtypes, which are Nephrotic or Nephritic, subdividing into several specific disease will be much more easier^[1][2] .The incidence of MPGN (as a lesion in renal biopsies) ranges from 1.4 to 9.3 cases per million population ^[1](pmp) per year and with few exceptions, the incidence has decreased over time.

• The incidence of MPGN is approximately 1.4 to 9.3 cases per million population per year worldwide.^[1]

• prevalence of MPGN is approximately 4.6-6.6 per 100,000 individuals worldwide.

• Patients of all age groups may develop MPGN.
• The incidence of MPGN increases with age,the median age at diagnosis is 31 years.
• MPGN commonly affects individuals from 2 to 80 year of age.

• MPGN usually affects individuals of the white and black race.
• Asian individuals are less likely to develop MPGN.

• MPGN affects men and women almost equally.
• Males are more commonly affected by MPGN than females.
• The men with specified MPGN are 50.8% of total glomerular diseases
• In females the incidence is 48.9% of total glomerular diseases.
• Type I MPGN disease affects women more often than men

• The majority of MPGN cases are reported in united kingdom.

• The next common region is united states.^[1][2][3]

By dividing glomerular diseases into two subtypes, which are Nephrotic or Nephritic, subdividing into several specific disease will be much more easier^[1][2] .The incidence of MPGN (as a lesion in renal biopsies) ranges from 1.4 to 9.3 cases per million population (pmp) per year and with few exceptions, the incidence has decreased over time^[4]

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

Membranoproliferative glomerulonephritis is associated with several diseases that can be categorized in to different groups. The most relevant conditions are chronic infections, autoimmune diseases, chronic liver disease (cirrhosis and alpha1-antitrypsin deficiency), chronic and recovered thrombotic microangiopathies, Paraprotein deposition diseases, and malignant neoplasms genetic mutations.

Conditions that increase the risk of MPGN incldude:

Conditions associated with a membranoproliferative pattern of injury are listed as follows:

• Immune complex–mediated disease

• Idiopathic forms of MPGN or of unknown association^[1]

  • MPGN type I
  • MPGN type II or dense deposit disease and PLD
  • MPGN type III

• Autoimmune diseases^[2][3][4]

  • Systemic lupus erythematosus (SLE)
  • Sjögren syndrome
  • Rheumatoid arthritis
  • Inherited complement deficiencies, in particular, C2 deficiency
  • Scleroderma
  • Celiac disease

• Chronic infections^[5]

  • Viral – Hepatitis B, hepatitis C, and cryoglobulinemia type II
  • Bacterial – Endocarditis, infected ventriculoatrial (or jugular) shunt, multiple visceral abscesses, leprosy
  • Protozoal – Malaria, schistosomiasis
  • Other infections – Mycoplasma, Lyme Disease^[6]

• Miscellaneous – Chronic liver disease (cirrhosis and alpha1-antitrypsin deficiency)

• Chronic and recovered thrombotic microangiopathies

• Healing phase of hemolytic uremic syndrome and/or thrombotic thrombocytopenic purpura
• Syndromes of circulating antiphospholipid (anticardiolipin) antibodies
• Radiation nephritis
• Nephropathy associated with bone marrow transplantation
• Sickle cell anemia and polycythemia
• Transplant glomerulopathy

• Paraprotein deposition diseases

• Glomerulonephropathies associated with cryoglobulinemia type I
• Waldenström macroglobulinemia
• Immunotactoid glomerulopathy
• Immunoglobulin light chain or heavy chain deposition diseases
• Fibrillary glomerulonephritis

• Genetic mutation
  • Deletion of Lys224 in regulatory domain 4 of Factor H
    • A study demonstrated that a delegation of a single Lys residue (K224) located within the complement regulatory region in domain 4 of Factor H will resulted in defected complement control . Mutant protein purified from the plasma of patients, so on laboratories test they showed severely reduced cofactor and decay-accelerating activity, as well as diminished attachment to the core complement component C3b. Albeit, cell-binding activity of the mutant protein was normal and comparable to wild-type Factor H.
• Malignant neoplasms

• Lymphoma
• Leukemia
• Carcinoma

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

The natural history of membranoproliferative glomerulonephritis (MPGN) is characterised by severity of clinical features which fluctuate often. Complete remission is seen in few cases only. Acute presentation and a slower reduction in renal function have seen more in children than adults. End stage renal disease is seen in approximately 40% of patients within 10 years of diagnosis. Features suggestive of an adverse outcome include nephrotic syndrome, renal dysfunction at onset, and persistent hypertension. Type II MPGN is associated with a worse prognosis. Recurrence occurs in 20 – 30% of type I and 80 – 90 % type II MPGN. The most common complications in patients who have MPGN are end-stage renal disease ESRD, edema, hypertension, infection with encapsulated bacteria hemophilus, Streptococcus, and Klebsiella species, thromboembolism and hyperlipidemia. Factors associated with poor prognosis of MPGN include Hypertension, elderly individuals and low GFR at 1st year of presentation.

The natural history of membranoproliferative glomerulonephritis (MPGN) is characterised by severity of clinical features which autonomously fluctuate, with very few cases of complete remission. Acute presentation and a slower reduction in renal function have seen more in children than adults. ESRD have been occurred among approximately 40% of patients within 10 years of diagnosis. Features suggestive of an adverse outcome include the nephrotic syndrome, renal dysfunction at onset, and persistent hypertension. Type II MPGN is associated with a worse prognosis, as is the presence of chronic interstitial damage on renal biopsy. In 20 – 30% of type I and 80 – 90 % type II MPGN, membranoproliferative glomerulonephritis may recur.

Common complications of MPGN include:

• End-stage renal disease (ESRD)
• Edema
  • Periorbital
  • Dependent edema
• Infection with encapsulated bacteria
  • Haemophilus species
  • Streptococcus species
  • Klebsiella species
• Thromboembolism events
  • There are several predisposing factor that can increase thromboembolism tendency, these factors are:
    • Decrease in anticoagulant factors such as, proteins C and S and antithrombin III
    • Increased platelet aggregability
    • Increase procoagulants proteins
    • Hyperlipidemia
    • Impaired fibrinolysis
• Malnutrition
• Anemia due to iron deficiency
• Hypocalcemia due to hyperparathyroidism secondary to vitamin D deficiency

Patients with MPGN type 1 and nephrotic syndrome have 50% vulnerability to develop end-stage renal disease (ESRD) within 10 years and 90% in 20 years. Type II MPGN is some how more aggressive and 50% of patients eventuate in ESRD after 10 years of diagnosis. Factors that are associated with poor prognosis of MPGN include:^[1][2][3]

• Hypertension at presentation
• Elderly individuals
• Low GFR at 1st year of presentation

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