Transcript Minimal Change Glomerulopathy

NAZMOON LAILA
Normal Renal Histology
The normal renal cortex contains
– glomeruli
– other vessels
– tubules and
– interstitium
Features in H&E :
– overall cellularity of the glomerulus
– the symmetry of the glomerulus
– the thickness of the capillary walls
Normal Histology
The renal cortex
renal cortex is easily identified even at low
magnification by the presence of renal
corpuscles, which are absent in the renal
medulla. However, the bulk of the cortex is
occupied by the proximal and distal
convoluted tubules. The arcuate arteries
and veins help to demarcate the cortex
from the medulla.
These micrographs compare the appearances of the proximal and distal
convoluted tubules. The proximal convoluted tubule (PCT) is a coiled tube
measuring approximately 14mm in length and random sections of PCT thus
occupy most of the renal cortex. Approximately 65% of the glomerular
filtrate is reabsorbed from the PCT, a function reflected in the structure of
the epithelial lining
As seen in micrograph (c), distal convoluted tubules DCT may be differentiated from
proximal convoluted tubules PCT by the absence of a brush border, a larger more
clearly defined lumen, more nuclei per cross-section (since DCT cells are smaller
than PCT cells) and paler cytoplasm (due to fewer organelles). In addition, sections of
DCT are less numerous than sections of PCT since the DCT is much shorter than the
PCT. In micrograph (d) the prominent brush border of the PCT is contrasted with the
lack of brush border in the DCT
The renal medulla :
renal medulla consists of closely packed tubules
of two types: the loop of Henle and the collecting
tubules and ducts as well as the vasa recta. The
loop of Henle is a continuation of the proximal
convoluted tubule. It dips down into the medulla,
where it loops back on itself and returns to the
cortex to it's own renal corpuscle, becoming the
first part of the distal convoluted tubule.
Acute nephritic syndrome is a glomerular syndrome dominated by
the acute onset of usually grossly visible hematuria (red blood cells
in urine), mild to moderate proteinuria, and hypertension; it is the
classic presentation of acute poststreptococcal glomerulonephritis.
The nephrotic syndrome is characterized by heavy proteinuria (more
than 3.5 gm/day), hypoalbuminemia, severe edema, hyperlipidemia,
and lipiduria (lipid in the urine).
Asymptomatic hematuria or proteinuria, or a combination of these
two, is usually a manifestation of subtle or mild glomerular
abnormalities.
Acute renal failure is dominated by oliguria or anuria (reduced or no
urine flow), with recent onset of azotemia. It can result from
glomerular, interstitial, or vascular injury or acute tubular necrosis.
Chronic renal failure, characterized by prolonged symptoms and
signs of uremia, is the end result of all chronic renal parenchymal
diseases.
Renal tubular defects are dominated by polyuria (excessive urine
formation), nocturia, and electrolyte disorders (e.g., metabolic
acidosis). They are the result of either diseases that directly affect
tubular structure (e.g., medullary cystic disease) or defects in
specific tubular functions. The latter can be inherited (e.g., familial
nephrogenic diabetes, cystinuria, renal tubular acidosis) or acquired
(e.g., lead nephropathy).
Urinary tract infection is characterized by bacteriuria and pyuria
(bacteria and leukocytes in the urine). The infection may be
symptomatic or asymptomatic, and it may affect the kidney
(pyelonephritis) or the bladder (cystitis) only.
Nephrolithiasis (renal stone) is manifested by renal colic, hematuria,
and recurrent stone formation.
Urinary tract obstruction and renal tumors represent specific
anatomic lesions with often varied clinical manifestations
Glomerular Diseases
constitute some of the major problems in nephrology; indeed, chronic
glomerulonephritis is one of the most common causes of chronic renal
failure in humans.
Glomeruli may be injured by a variety of factors and in the course of a
number of systemic diseases.
Systemic immunologic diseases such as systemic lupus erythematosus
(SLE), vascular disorders such as hypertension and polyarteritis nodosa,
metabolic diseases such as diabetes mellitus, and some purely hereditary
conditions such as Fabry disease often affect the glomerulus. These are
termed secondary glomerular diseases to differentiate them from disorders
in which the kidney is the only or predominant organ involved.
The latter constitute the various types of primary glomerulonephritis or,
because some do not have a cellular inflammatory component,
glomerulopathy.
However, both the clinical manifestations and glomerular histologic changes
in primary and secondary forms can be similar.
Various types of glomerulonephritis are characterized by one or
more of four basic tissue reactions.
Some inflammatory diseases of the glomerulus are characterized by
an increase in the number of cells in the glomerular tufts. This
hypercellularity is characterized by one or more combinations of the
following:
Cellular proliferation of mesangial or endothelial cells
Leukocytic infiltration, consisting of neutrophils, monocytes, and, in
some diseases, lymphocytes
Formation of crescents. These are accumulations of cells composed
of proliferating parietal epithelial cells and infiltrating leukocytes. The
epithelial cell proliferation that characterizes crescent formation
occurs following an immune/inflammatory injury (see later). Fibrin,
which leaks into the urinary space, often through ruptured basement
membranes, has been long thought to be the molecule that elicits
the crescentic response. such as interleukin-1, tumor necrosis
factor, and interferon-γ.
Basement Membrane Thickening. By light microscopy,
this change appears as thickening of the capillary walls,
best seen in sections stained with periodic acid-Schiff
(PAS).
By electron microscopy, such thickening can be resolved
as one of two alterations: (1) deposition of amorphous
electron-dense material, most often immune complexes,
on the endothelial or epithelial side of the basement
membrane or within the GBM itself. Fibrin, amyloid,
cryoglobulins, and abnormal fibrillary proteins may also
deposit in the GBM; or (2) thickening of the basement
membrane proper, as occurs in diabetic
glomerulosclerosis.
.
Hyalinization and Sclerosis.
Hyalinization, or hyalinosis, as applied to the glomerulus, denotes
the accumulation of material that is homogeneous and eosinophilic
by light microscopy.
By electron microscopy, the hyalin is extracellular and consists of
amorphous substance, made up of plasma proteins that have
exuded from circulating plasma into glomerular structures.
This change contributes to obliteration of capillary lumina of the
glomerular tuft (a feature of sclerosis). Hyalinosis is usually a
consequence of endothelial or capillary wall injury and typically is
the end result of various forms of glomerular damage. Additional
alterations include intraglomerular thrombosis or accumulation of
lipid or other metabolic materials
All the glomerular capillaries should be
about the same thickness, which is very
thin (almost wispy).
With normal cellularity, cell nuclei are not
clustered or overlapping. Clusters of cells,
especially away from the hilum, indicate
abnormal hypercellularity. Increased cells
within the lumens of capillaries indicate
leukocyte infiltration or, rarely, an
angiotrophic lymphoma.
In the cortex but not the medulla, the
tubules should be almost back to back, i.e.
the tubular basement membranes should
be almost touching. There is very little
interstitium in the cortex, therefore, if there
is space between the tubules, there is
something wrong in the tubulointerstitial
compartment (e.g. edema or fibrosis).
Intrarenal arteries have very little intima,
i.e. there is little or no space between the
endothelium and the muscularis.
Pathologic processes expand the arterial
intima, e.g. collagen in arteriosclerosis and
proteinaceous insudate in an acute
thrombotic microangiopathy.
(green = epithelial cells, yellow = endothelial cells, red = mesangial cells).
Visceral epithelial cells line the capillary walls.
Parietal epithelial cells line Bowman's capsule,
and are continuous with the proximal tubular
epithelial cells. Endothelial cells line capillary
lumens. Mesangial cells are in the middle
(meso) between the capillaries (angis). The
mesangial cells are modified smooth muscle
cells that are continuous with the vascular
smooth muscle cells in the hilar arterioles. As
such, they have a contractile capability and can
tug on the edges of the capillaries and thus
control blood flow through the glomerulus
Mesangial cells also produce a variety of
cytokines when stimulated, and are
capable of phagocytosis. There is a route
for trafficking of debris through the
mesangium that begins in the
subendothelial zone and enters the
mesangium and then passes through
physiologic if not actual channels through
the matrix to the hilum.
PAS
Trichrome
H&E
Jones silver stains
The silver stain accentuates collagenous
structures, e.g., in the glomerulus, the mesangial
matrix and the glomerular basement membrane.
The PAS stain also accentuates matrix and
basement membrane constituents, as does the
blue or green component on the trichrome stain.
In certain circumstances the trichrome stain
demonstrates immune deposits as fuchsinophilic
(red) structures.
The peripheral endothelial cell cytoplasm,
which has pores through it, looks like a
little string of sausages on cross section.
This allows recognition of the lumenal side
of the capillary wall. The visceral epithelial
cells, or podocytes, have foot processes
that are intact in normal glomeruli and
often effaced in proteinuric conditions.
The glomerular basement membrane has
3 ultrastructural zones that can be
disturbed in various glomerular diseases:
the lamina densa in the middle, the lamina
lucida (rara) externa and the lamina lucida
(rara) interna.
The glomerular basement membrane does not
completely enclose the lumen, unlike the
endothelial basement membrance in most
vessels, but rather splays out over the
mesangium to become the paramesangial
basement membrane. This leaves a functional
gap where materials from the capillary lumen or
subendothelial zone (having passed through the
endothelial pores) can directly enter the
mesangium without traversing the basement
membrane. This explains why the mesangium is
a preferential sequestration point for some types
of debris, including immune complexes.
The endothelial cell nucleus sits over the
origin of the mesangium, which is where it
is usually found. A few pores through the
endothelial cytoplasm can be seen. The
glomerular basement membrane lamina
lucida externa is the thin lucent zone just
under the foot processes of the visceral
epithelial cell. The bulk of the basement
membrane is the lamina densa.
The pores through the endothelial cell are below
the basement membrane. The thickness of the
glomerular basement membrane lamina densa
is about 5-6 times thicker than the lamina lucida
externa in this particular electron micrograph.
The lamina lucida externa thickness is a useful
landmark that can be used to assess the normal
thickness of the glomerular basement
membrane. The thickness of the lamina densa is
important in making the diagnosis, for example,
of thin basement membrane nephropathy and
diabetic glomerulosclerosis.
Another internal reference point for basement
membrane thickness is an intact foot process. If
you average the width of intact foot processes
and then turn that 90 degrees, that is about the
normal thickness of the laminar densa.
Therefore, if you compare the thickness of the
lamina densa to that of the lamina lucida externa
or to an intact foot process, you can determine
whether the basement membrane is normal or
abnormal thickness.
Minimal Change Glomerulopathy
There are many synonyms for minimal change
glomerulopathy, e.g., minimal change disease,
lipoid nephrosis, nill disease.
No abnormality.
Sometimes there may be a little bit of mesangial
hypercellularity in a few segments. Otherwise,
any scarring, any infiltration of leukocytes, any
necrosis, or any other substantial structural
changes in glomeruli rule out a diagnosis of
minimal change glomerulopathy
Slide 13 is a representative immunofluorescence micrograph of
the immunohistology of minimal change glomerulopathy, i.e.,
background staining. There are occasional specimens that will
have small amounts of exclusively mesangial immunoglobulin
(especially IgM) or complement accumulation that can still be
designated minimal change glomerulopathy. A little bit of
mesangial IgM and/or C3 without ultrastructural evidence for
electron dense deposits is tolerable for a diagnosis of minimal
change glomerulopathy. When groups of patients with
absolutely no immunofluorescence findings have been
compared to those that have low levels of IgM dominant
mesangial deposits without electron dense deposits, they act
no differently with respect to their clinical response to steroids
and long term outcomes. Well defined mesangial electron
dense deposits, however, worsen the prognosis for response to
steroids or spontaneous remission. Thus, if there are electron
dense deposits, minimal change glomerulopathy is not an
appropriate diagnoses.
Effacement of visceral epithelial foot
processes and epithelial microvillous
transformation. Microvillous transformation
of epithelial cytoplasm often accompanies
effacement. The effacement of foot
processes and microvillous transformation
are not specific for minimal change
glomerulopathy.
Foot process effacement is characteristic for
minimal change glomerulopathy and is required
for the pathologic diagnosis of this disease;
however, this same change is present in any
patient with substantial proteinuria of any cause.
Therefore, the diagnosis of minimal change
glomerulopathy is one of exclusion, i.e., these
ultrastructural changes should be present in the
absence of light microscopic, immunohistologic
or other ultrastructural features of any other
cause of proteinuria.
almost complete effacement of the visceral
epithelial foot processes. There is condensation
of the epithelial cytoskeleton near the basement
membrane. If you don't know what this is, you
can mistake it for subepithelial electron dense
deposits, suggesting membranous
glomerulopathy. It is actin condensation that
takes place inside of visceral epithelial
cytoplasm when there is effacement of foot
processes, suggesting that there is movement of
cytoplasmic structures during the effacement
event.
Membranous Glomerulopathy
Membranous glomerulopathy is the most common cause for the
nephrotic syndrome in adults, whereas, minimal change
glomerulopathy is the most common cause for the nephrotic
syndrome in children. Even though membranous glomerulopathy is
the most common cause in adults, it only accounts for about 1/3 of
adults with nephrotic syndrome in my renal biopsy population. The
frequency of membranous glomerulopathy in other series ranges
from around 20% to around 50%, and most series are under 50%.
Thus, in an adult with the nephrotic syndrome, if you guess
membranous glomerulopathy every time, you are going to be wrong
about 2/3 of the time. Therefore, in adults with nephrosis, most
nephrologists will biopsy to identify the underlying disease
From age 16 to 65, membranous glomerulopathy is rather frequent,
but its highest frequency is in the 40-60 year old age group.
early stage: If you don't have a good
internal reference as to the thickness of
capillary loops, it is hard to look at a
membranous glomerulopathy biopsy
and be sure there is something wrong
by light microscopy, especially during
early stages to the disease
a late stage membranous
glomerulopathy with markedly
thickened capillary walls.
the very thick capillary wall of an overt case of
membranous glomerulopathy can be recognized. On a
trichrome stained section (middle panel), if you have a
good stain and if the stage of the disease is just right and
there are big deposits, you can see the subepithelial
immune complex deposits as fuchsinophilic (red)
granular deposits. The blue basement membrane is
beneath the deposits and there are projections of blue
between them. On a silver stained section, and
sometimes on a well- stained PAS stained section, as
shown in the panel on the right, you can see the socalled spikes of basement membrane that project
between the deposits in certain stages of membranous
glomerulopathy, in particular stage II.
The characteristic lesion of membranous
glomerulopathy is deposition of immune
complexes in the subepithelial zone. In later
stages of the disease, the deposits are
transformed into intramembranous deposits.
19diagrams a stage II lesion with regularly
distributed deposits with projections of basement
membrane between them. There also is
effacement of foot processes in microvillous
transformation.
.
The electron micrograph (Slide 20) of a
stage II membranous lesion demonstrates:
capillary lumen, endothelial cytoplasm,
original basement membrane,
subepithelial deposits (with actin
condensation in the overlying epithelium),
and projections of basement membrane
material between the deposits
In stage I there are no basement membrane
projections adjacent to deposits. In stage II there
are GBM projections between deposits. In stage
III, the deposits become incorporated in the
basement membrane. In stage IV, the deposits
start to fade away leaving lucent gaps and a
thickened basement membrane. The stage V
lesion, paradoxically, has a normal subepithelial
zone of the basement membrane, which has
been repaired, and the disturbance has been
pushed to the subendothelial zone.
demonstrates the typical immunofluorescence
microscopy pattern of membranous glomerulopathy, in a
panel adjacent to a low magnification electron
micrograph. The grains seen by immunofluorescence
microscopy correspond to the electron dense deposits.
Typically, the granular staining of membranous
glomerulopathy is diffuse and global(Slide 22a). Diffuse
means all of the glomeruli are involved, as opposed to
focal, which means that some glomeruli are involved and
some are not. Global means that all the glomerular
segments and capillaries are involved in a given
glomerulus, as opposed to segmental, which means that
only some of them are.
Typically, membranous glomerulopathy has
diffuse global granular staining of capillary
walls.
The composition of immune deposits is
almost always IgG-dominant. Usually there is
some IgM and IgA. C3 staining is usually
very low intensity in idiopathic(primary)
membranous glomerulopathy,
a post-infectious glomerulonephritis in which
there is usually intense C3 staining along
with very low intensity or absent IgG
staining.