Membranoproliferative glomerulonephritis: Difference between revisions

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== [[Membranoproliferative glomerulonephritis overview|Overview]] ==
== [[Membranoproliferative glomerulonephritis overview|Overview]] ==
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== [[Membranoproliferative glomerulonephritis pathophysiology|Pathophysiology]] ==
== [[Membranoproliferative glomerulonephritis pathophysiology|Pathophysiology]] ==
==== PATHOGENESIS ====
The pathogenesis of MPGN is not yet clearly understood. It is believed that type I MPGN results from chronic antigenemia and the generation of nephritogenic immune complexes that preferentially localize to the subendothelial spaces. The precise nature of the putative antigen(s) in most patients with type I MPGN is unknown; however, a specific pathogenic antigen can sometimes be demonstrated in the glomerular lesions [7]. Recent studies have demonstrated the contribution of 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 [8, 9]. The immune complexes activate the complement system via the classical pathway, leading to the generation of chemotactic factors (C3a, C5a) that mediate the accumulation of platelets and leukocytes and of terminal components (C5b-9) that directly induce cell injury. Leukocytes release oxidants and proteases that mediate capillary wall damage and cause proteinuria and a fall of glomerular filtration rate. Cytokines and growth factors released by both exogenous and endogenous glomerular cells lead to mesangial proliferation and matrix expansion [10].
The pathophysiologic basis for type II MPGN seems to be the uncontrolled systemic activation of the alternative pathway of the complement cascade [11, 12]. In most patients, loss of complement regulation is caused by the C3 nephritic factor (C3NeF), an immunoglobulin (Ig)G autoantibody that binds and prevents the inactivation of C3 convertase (C3bBb) of the alternative pathway, thereby resulting in the perpetual breakdown of C3. A further 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 [12].
Type II MPGN may occur in association with two other conditions, either separately or together: acquired partial lipodystrophy (APD) and macular degeneration. The abnormal activation of the alternative pathway of the complement system is the common link to these seemingly disparate diseases [13]. Acquired partial lipodystrophy is associated with the presence of circulating C3NeF, which can cause a complement-mediated lysis of adipocytes that in turn produce high concentrations of factor D, also called adipsin. Factor D cleaves factor B, activating the alternative complement pathway. By analogy, C3NeF may cause damage to glomerular cells that produce the complement. Nonetheless, C3NeF can occur in apparently healthy individuals and in patients with other types of glomerular diseases. In addition, C3NeF does not always correlate with the occurrence or progression of type II MPGN, suggesting the role of other factors [12].
Complement perturbation in type III MPGN is thought to be related to a slow-acting nephritic factor that stabilizes a properdin dependent C5-convertase, (Cb3)2BbP, activating the terminal pathway; hence, the term nephritic factor of the terminal pathway (NeFt) [14]. This nephritic factor has not been reported in healthy subjects, unlike C3NeF. In addition, the deposits observed 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 [15].
The mechanism of renal injury in HCV-associated cryoglobulinemia remains elusive. An estimated 50–60% of patients with chronic HCV infection develop type II cryoglobulins, which are composed of a complex of an IgM kappa monoclonal antibody with rheumatoid factor activity directed against a polyclonal anti-HCV IgG. However, only a minority (10–20%) of such patients with detectible cryoglobulinemia have clinical manifestations of cryoglobulinemic MPGN [2]. 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.


== [[Membranoproliferative glomerulonephritis causes|Causes]] ==
== [[Membranoproliferative glomerulonephritis causes|Causes]] ==

Revision as of 21:08, 10 June 2018

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Membranoproliferative glomerulonephritis
ICD-10 N00-N08 with .2 suffix
ICD-9 581.2, 582.2, 583.2
MeSH D015432

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Overview

Membranoproliferative Glomerulonephritis (MPGN) is a relatively uncommon inflammatory glomerulopathy that can cause chronic nephritis. Based on the histological pattern of glomerular injury it has been described as a chronic kidney disease found mostly in children and young adults. 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 characterized by mesangial proliferation and expansion, lobularization of the glomerular tufts and double contours which can be caused by many disease states [1]. Glomerular injury occurs due to deposition of immune complexes on the glomerular mesangium or on the glomerular basement membrane. MPGN has been categorized into 3 types based on the histological pattern of glomerular damage. Clinically, MPGN often present with hematuria, varying degrees of proteinuria, with or without Glomerular filtration rate impairment depending on the severity of glomerular injury, and the underlying etiology.

Historical Perspective

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 using the special stain periodic acid–silver methenamine (now known as Jones stain). Jones fully illustrated the special features of this lesion such as lobular glomerulonephritis (now known as membranoproliferative glomerulonephritis), lipoid nephrosis (now known as minimal change disease), and chronic glomerulonephritis (now known as focal and segmental glomerulosclerosis). The thickening of the capillary wall and alteration in basement membrane structure, so characteristic of the membranous lesion, were convincingly shown . 

The electron-dense subepithelial location of the were also subsequently identified by Movat and McGregor in 1959 using electron microscopic methods applied to renal biopsy specimens in 1957. Mellors  in 1957 had identified the third component of the unique lesion of membranous glomerulonephritis; namely, 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 delineated. These are still the fundamental features used today to identify membranous glomerulonephritis, now called Membranoproliferative glomerulonephritis.

Classification

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 [2];

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

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  1. Lionaki S, Gakiopoulou H, Boletis JN (2016). "Understanding the complement-mediated glomerular diseases: focus on membranoproliferative glomerulonephritis and C3 glomerulopathies". APMIS. 124 (9): 725–35. doi:10.1111/apm.12566. PMID 27356907.
  2. Sethi S, Fervenza FC (2011). "Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification". Semin Nephrol. 31 (4): 341–8. doi:10.1016/j.semnephrol.2011.06.005. PMID 21839367.