syndrome (NS) is the collective term given to patients who experience a variety
of symptoms caused by glomerular damage in the the kidneys. The
glomerulus is a cluster of small blood vessels called capillaries located within the Bowman’s capsule, and together this unit constitutes the renal corpuscle
(Fig 1)(1). It is positioned at the
beginning of a nephron in the kidney,
acting as the basic filtration unit. Glomerular capillary walls
are composed of three structures: the endothelial cells, the glomerular basement membrane (GBM) and epithelial cells (podocytes;
attached to each other via network of slit diaphragms) and these together are
called the filtration barrier (1,2). Passage of plasma proteins into the tubules
is normally restricted due to the size and charge of this barrier. (Fig 2).
During filtration, blood enters via the afferent arteriole and flows
into the glomerulus where filterable blood components, such as water and
nitrogenous waste, enter the glomerulus, and non-filterable components like
cells and proteins like albumin, will exit via the efferent arteriole.
Filtration happens depending on the charge and size of the component. Filterable components accumulate in the Bowman’s space
and are known as the glomerular filtrate. Next, reabsorption occurs, in which
molecules and ions are reabsorbed into the circulatory system(2).
fluid passes through the other components of the nephron as water and ions are
removed. The end product of these processes is urine, which is fundamentally all
the components that were not reabsorbed during glomerular filtration or tubular
reabsorption. Glomeruli usually prevent around 150mg of protein
being absorbed from the blood into the urine(2). In NS the glomeruli
are damaged and kidney function is impaired. Proteins will leak into the urine and
blood loses its capacity to absorb excess fluid from the body. The amount of
protein lost amounts to roughly 3.5 grams which is around 25 times more than
the normal amount. The proteins that are lost are primarily albumin
but also opsonins, immunoglobulins, erythropoietin,
transferrin, hormone-binding proteins and antithrombin III. Deficiency of these
proteins results in various complications(2).
NS carries no
age predominance but is usually first diagnosed in children aged between
two and five years old. Around 1 in
every 50,000 children in the UK are diagnosed with the condition each year with
it being the most common chronic renal disease found in children. There is also a
slight male predominance affecting boys more than girls by a ratio of 2:1(3). There is no
evidence of gender predominance in adults(2).
Genetic studies show higher reoccurrence of NS in families with positive
cases, families with a history of allergies
and diabetes or those of Asian and African American ethnicity, although
it’s ambiguous as to why this is the case (2).
NS is defined
as the presence of marked proteinuria (increased protein in the urine) at a
rate of >40 mg/m2/hr and hypoalbuminaemia (decreased albumin levels in
the blood) (3). Presence of hyperlipidaemia (increased fat and cholesterol levels in
the blood) and oedema (swelling in the lower body) can also be seen(4).
occurs because of changes to the capillary endothelial cells, the glomerular
basement membrane (GBM), or podocytes, which as mentioned above, normally
filter serum protein selectively by size and charge(4). Damage to any one
component has a knock-on effect on the function of the other two components.
One study shows that endothelium activation and loss of selectivity
leads to prolonged exposure of podocytes to proteins(5). This result in the
activation of renin-angiotensin in podocytes and alteration of size
selectivity. In normal kidney function, glomerular capillary walls are
richly coated with glycoclax which has a negative charge. This repels albumin
molecules from filtering through, due to their negative charge. In NS, the
endothelium has a reduction in negative charge, thus allowing protein molecules
to freely pass through(2,5).
correlates with marked hypoalbuminaemia. Albumin that has passed through the
GBM due to glomerular injury is lost in the urine. In response to marked proteinuria, albumin synthesis by the liver is increased
but this is insufficient to prevent the decrease in serum albumin
concentration. This leads to some of the other consequences of NS including
hypercholesterolaemia and hypercoagulability(2,3,5).
of oedema formation is not fully understood. One theory is that the lack of
albumin causes a reduced oncotic pressure. This in turn causes a
reduction in the circulating blood volume which again stimulates the
renin-angiotensin-aldosterone system of the kidney to retain salt and water and
circulating them to the tissues causing swelling(6).
clinical signs that Furthermore, affected individuals will also experience
classic symptoms like tiredness, lethargy and a poor appetite. Children
can experience nausea and diarrhoea. Urine can appear foam or frothy as a
result of hypoalbuminaemia. Affected individuals may have increased
susceptibility to infections and will be susceptible to the risk of thrombosis
or the formation of blood clots(4).
disorders can cause damage to the glomeruli, resulting in NS. These disorders
are classified as either primary; being a disorder specific to the kidneys, or
secondary; being a renal manifestation of systemic diseases that affect other
organs. (Table 1). The initial cause varies between adults and children. Minimal change
disease is the most common cause of glomerular damage in children whereas the
primary cause in adults is focal glomerulosclerosis and membranous nephropathy(1-6).
More than 50 percent of NS cases in adults have secondary
causes, with diabetes being the most common. Three of the main primary
disorders have been discussed further in this review.
disease (MCD) is the most common cause of NS in children accounting to around
80% of reported cases. In adults, it accounts for 10-15% of reported cases(6,7).
it is characterised by minimal changes on light microscopy.
However, with electron microscopy, the disappearance of foot process of
podocytes with microvillous transformation is observed(Fig.3). The cause of MCD
is unknown but one hypothesis is the involvement of T-lymphocytes.
Dysfunctional T-cells are thought to produce increasing levels of glomerular
permeability factor which directly affects the capillary walls, resulting in
the effacement of podocytes(7).
glomerulosclerosis (FSGS) is another type of glomerular damage characterised by
scarring within the glomeruli (Fig.4). The distribution of scarring is focal
(affecting only a few glomeruli) and segmental (affecting one part of an
individual glomerulus) hence the name(9). FSGS can be either primary (scarring
occurred on its own) or secondary (caused by another medical condition). Several
studies have concluded that the scarring is initiated by podocyte injury (9,10).
Genetic factors play a key role in the pathogenesis of FSGS. Two common genes
that initiate podocyte injury are the NPHS1
and NPHS2 gene which code for the
slit diaphragm proteins nephrin and podocin respectively. These proteins are expressed both on the cell surface and
intracellularly. They are joint to the cytoskeleton of the podocyte and their
disruption affects the slit diaphragm and the integrity of all the foot
processes(11). Another study has shown the higher risk of incidence of FSGS in
in the African-American population who have alterations in the APOL1 gene(12). There are also many proposed theories that
suggest T cell-mediated circulating permeability factors play a key role in
initiating podocyte injury and this has been observed in renal patients who have undergone kidney transplantation(13).
Histologically, renal biopsies will show prominent scarring
lesions occurring in some tufts within the glomerulus indicating that it is
segmental. Affected glomeruli will show increased mesangial matrix and damaged
capillary lumens. Hyaline mass deposits will be present, representing the
entrapment of plasma proteins and lipids. They will appear as a glassy
homogenous smooth appearance under light microscopy(11). Immunohistochemistry can show the presence of
trapped IgM and C3 complement proteins as a result of entrapment. Electron
microscopy will show effacement of foot processes. Adhesions of the capillary tuft to the
Bowman’ s capsule is a common feature (10).
As there are several histological subtypes of FSGS, a study in 2014 by
the Columbia University derived a classification system based on morphology
(Table 2)(14). This classification grouped morphology into five categories;
collapsing variant, tip variant, cellular variant, perihilar variant and not
otherwise specified(NOS) variant(Fig 5)(14).
nephropathy (MN) is the most common primary cause of NS in adults however can
also be secondary to infections, systemic lupus erythematosus, drugs and
malignancy. It is characterised by the accumulation of immune deposits on the
GBM. Light microscopy with haematoxylin and eosin (H&E) staining will show
the thickening of GBM with normal glomerular cellularity (Fig 6). Silver
staining will show spikes of basement membrane projecting away from the lumen.
Immunofluorescence microscopy will show positive staining for IgG and C3
complement similar to that of FSGS.
Under electron microscopy, discrete subepithelial deposits can be seen
with podocyte foot process effacement. MN is a progressive disease and normal
features can be seen during the early stages of the disease, which steadily
progress as the prognosis worsens, hence each phase is categorised by stages
depending on the appearance by microscopy (Table 3)(16)