Glomerular diseases

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The glomerulus is the target of many disease processes, leading to temporary or
permanent impairment of function.
As a highly specialized component of the blood circulatory system, responsible for
ultrafiltration, the glomerulus can be damaged by :
generalized vascular disease, particularly hypertension, vasculitis, and diabetes mellitus;
immunological disorders, particularly where immune complexes are deposited in glomerular capillary
depositions of foreign material, e.g. amyloid
The term glomerulonephritis is traditionally used to describe the group of diseases in which
the primary pathology is some sort of structural abnormality in the glomerulus.
Despite the suffix -itis, most are not characterized by inflammatory changes. Damage to the glomerulus
may be severe, leading to permanent scarring, in which case the associated tubule atrophies.

Alternatively some conditions produce temporary abnormality and, following resolution,
there is restoration of nephron function.

Glomerular disease is classified according to the histological pattern of damage seen on renal biopsy, hence a knowledge of this aspect of histopathology is needed to understand disease.
This arrangement is supplemented by further classification according to aetiology of disease.
In many cases the cause of glomerular disease is uncertain and some types of glomerular disease are considered idiopathic.

The glomerulus has a limited set of histological responses to damage
There are four significant components of the glomerulus:
1 The endothelial cells lining the capillary.
2 The glomerular basement membrane (GBM).
3 The mesangium, which is the supporting 'mesentery' to the capillary, comprises mesangial cells (phagocytic support cells) and associated extracellular material (mesangial matrix).
4 The epithelial cells or 'podocytes', which form an outer coating to the capillary. These cells are in contact with the outer surface of the basement membrane via a series of foot processes.
At the vascular hilum of the glomerulus, the epithelial cells are continuous with the
flattened epithelial cells lining Bowman's capsule.
Five main patterns of response to damage are seen in the glomerulus, combinations of which describe
all types of glomerular disease.
Proliferation of endothelial cells leads to occlusion of capillary lumina, often with neutrophils
present. This proliferation reduces the flow through glomeruli and correlates with oliguria and uraemia.
Proliferation of mesangial cells, which is usually associated with increased production of matrix,
is a common feature of many glomerular diseases.
In some cases this may regress once the acute episode is over, in others the production of excess mesangial matrix over many years eventually leads to sclerosis (hyalinization) of all or part of the
glomerular tuft, with loss of capillary lumina.
Basement membrane thickening may be due to the deposition of an abnormal substance
(immune complexes or amyloid), synthesis of new basement membrane material, insinuation of mesangial
cytoplasm and matrix, or a combination of these causes.
Capillary wall necrosis, usually fibrinoid necrosis, occurs in diseases
in which there is severe acute capillary wall damage, e.g. necrotizing vasculitis and
accelerated (malignant) hypertension.
Crescent formation is an important reaction to severe glomerular capillary damage,
stimulated by leakage of blood and fibrin into the urinary space. Crescents are formed by
proliferation of the epithelial cells that line the Bowman's capsule, which crush the glomerulus,
and lead to permanent loss of the whole nephron The presence of widespread crescents is a poor
prognostic sign, relating to severe and usually rapidly progressive disease.

Glomerular disease may not affect all glomeruli in a uniform manner
Most glomerular diseases affect different glomeruli to varying degrees, with only
a small number of diseases affecting all glomeruli in a uniform manner. This explains
how some glomerular diseases cause sudden acute renal failure (disease affects all
glomeruli in a uniform manner), whereas others cause a selective partial renal failure syndrome
(disease affects small areas in a small proportion of glomeruli). A nomenclature has been agreed
for the various patterns of disease
Thus a glomerular disease may be described as 'diffuse global', 'diffuse segmental',
'focal global' or 'focal segmental'.
The vast majority are either 'diffuse global' or 'focal segmental'.
Patterns of glomerular disease.}

(a) Global: affecting the whole of the glomerulus uniformly.
(b) Segmental: affecting one glomerular segment, leaving other segments unaffected.
(c) Diffuse: affecting all glomeruli in both kidneys.
(d) Focal: affecting a proportion of glomeruli, with others unaffected.
Pathogenesis of acute diffuse proliferative glomerulonephritis


Acute diffuse proliferative glomerulonephritis usually presents as the nephritic syndrome
Acute proliferative glomerulonephritis is a diffuse global disease of glomeruli.
It is caused by deposition of immune complexes in glomeruli, which is stimulated by a preceding
infection. Although infection is most commonly streptococcal, a range of bacterial, viral and
protozoal infections can also stimulate this pattern of disease.
Histologically, there is increased cellularity of the glomerulus, with four main features:
Proliferation of endothelial cells produces occlusion of capillary lumina, leading to reduced
glomerular filtration, with rising blood pressure and blood levels of nitrogenous components
(urea and creatinine).
Presence of immune complexes in lumps on the epithelial side of GBM.
Presence of neutrophil polymorphs in capillaries.
Mild mesangial cell proliferation
(a) In diffuse acute proliferative glomerulonephritis there is endothelial proliferation with neutrophils,
sub-epithelial lumpy immune complex deposits, and mesangial cell increase.

(b) The glomerulus is hypercellular due to proliferation of endothelial and mesangial cells. Glomerular
capillary lumina cannot be identified because they are obliterated by the proliferating endothelial cells.
The immune complex deposits can only be seen by electron microscopy.
Pathogenesis of membranous nephropathy
The natural history of membranous nephropathy
Membranous nephropathy nephropathy presents with proteinuria and the nephrotic syndrome
Characterized by the presence of immune complex deposits in the basement membrane of all segments
of all glomeruli, membranous nephropathy is diffuse and global. The aetiology of immune
complexes in membranous disease is uncertain (see pink button below). Unlike diffuse proliferative
glomerulonephritis, there is no inflammation or associated endothelial or epithelial proliferation,
although the mesangium may be increased.

The disease passes through three pathological stages:
1 Immune complex deposited on epithelial side of basement membrane.
2 New basement membrane deposited around immune complex deposits.
3 Immune complex deposits disappear, leaving thickened 'lacy' basement membrane.
The abnormality of the basement membrane renders it unusually permeable; it no longer selectively
retains proteins, leading to heavy proteinuria and the nephrotic syndrome. With time,
the abnormal glomeruli develop increase in mesangial matrix produced by the mesangial cells. This,
together with membrane thickening, causes gradual hyalinization of the glomeruli and death of
individual nephrons. This process takes place over many years and, from a nephrotic syndrome,
the patient may develop chronic renal failure with uraemia.
(a) In membranous nephropathy there are electron-dense deposits (sub-epithelial), and slight mesangial
increase. In late-stage disease there is removal of deposits, leaving a thick 'lacy' membrane, and
increasing mesangial matrix deposition.
(b) Electron micrograph of a basement membrane thickened by deposition of antigen-antibody
complexes on the epithelial side of the basement membrane, from a patient with membranous
nephropathy who presented with the nephrotic syndrome.
(c) Methenamine silver staining shows mesangial matrix and basement membrane material. In membranous
nephropathy, new basement membrane material is deposited around immune complexes, and can be
seen as spaced black spikes and dots on the outer surface of the membrane.
Pathogenesis of MPGN Membranoproliferative glomerulonephritis
Diffuse membranoproliferative ('mesangiocapillary') glomerulonephritis often
presents as a nephrotic or a mixed nephritic/nephrotic syndrome
Membranoproliferative glomerulonephritis (MPGN), also called mesangiocapillary glomerulonephritis,
is a pattern of glomerular reaction to complement abnormalities. Some are secondary to systemic
disorders, such as SLE, infective endocarditis, malaria and infected ventricular CSF shunts,
but the major group is idiopathic, divided by clinical and pathological features into two types
(Type I and Type II), each with a particular pathogenesis.
As the name implies, the common factors in this process are mesangial proliferation and
basement membrane thickening as the main structural abnormalities.
The basement membrane abnormality is responsible for the clinical symptoms of proteinuria
or a full nephrotic syndrome.
Because there is cellular proliferation, patients may also develop haematuria or a nephritic syndrome.
A mixed nephrotic/nephritic syndrome is seen in some cases.

Goodpasture's syndrome

Focal segmental proliferative glomerulonephritis ental proliferative glomerulonephritis can
be either primary or secondary
In almost every case, focal glomerulonephritis is also 'segmental', only occasional lobules
of the glomerular tuft being involved in disease.
In this type of reaction, there is cellular proliferation affecting only one segment of the
glomerular tuft and occurring in only a proportion of all glomeruli. As there is cellular proliferation,
patients tend to present with haematuria or the nephritic syndrome with proteinuria.
In some cases the focal glomerulonephritis can be a stimulus for crescent formation.
This reaction is caused by several different diseases, divisible into two groups: primary types
(IgA mesangial disease and Goodpasture's syndrome), and those associated with other systemic diseases,
which are classed as secondary focal segmental glomerulonephritis.
In the evaluation of these cases, electron microscopy & immunohistochemistry are essential
to establish the deposition of immune complexes characteristic of different types.
Of the primary types, IgA mesangial (Berger's)disease is the most common cause of
glomerulonephritis in adults. It usually presents with recurrent haematuria or persistent
proteinuria. In a small proportion of cases there is a nephritic syndrome.
There is segmental and focal proliferation of glomerular tuft, and electron microscopy shows
deposits of IgA in the mesangium and at the junction between the mesangium and the basement
membrane (paramesangial). Tuft proliferation is followed by mesangial matrix deposition and
eventual sclerosis of the damaged segment.
Around 25% of patients progress to eventual chronic renal failure over a period of many years,
when sufficient segments of sufficient glomeruli have been damaged to lead to
glomerular sclerosis and nephron death.
The pathogenesis of the disease is uncertain.
The IgA that is deposited in the mesangium almost certainly comes from bone marrow rather than
from mucosal sites. Consequently, previous suggestions that chronic mucosal allergies
predispose to the condition are unlikely to be correct.

Minimal change disease is a common cause of nephrotic syndrome in childhood
Minimal change disease is mainly seen in children under the age of 6 years, in whom it causes
proteinuria and a nephrotic syndrome. In adults the condition is less common, but still accounts
for 10-25% of cases of nephrotic syndrome.
The characteristic feature, and the reason for the name, is that by light microscopy there is
nothing abnormal to see in the glomeruli.
By electron microscopy there is fusion of the foot processes of podocytes
Immune complexes and deposits are not seen.
Tubules may show accumulation of lipid in lining cells, giving rise to the old-fashioned
alternative name of lipoid nephrosis, which is sometimes still used.
Treatment with steroids usually brings about remission of disease within 2 weeks, although
relapse is frequent when steroids are stopped.
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We give here simplified and accurate information about the disease

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Revised: 02-11-2014.