RENAL PATHOLOGY

Minimal Change Disease

One of the two glomeruli shown contains two small peripheral

Glomeruli are normal by light microscopy in minimal change
disease, as shown in this biopsy. The glomerular basement
membrane is thin and delicate, and mesangial cellularity and
matrix are within normal limits. There was no interstitial
fibrosis and no segmental sclerosis in any of the glomeruli
sampled. However, the possibility of unsampled focal
segmental glomerulosclerosis (FSGS) cannot be completely
excluded when only a small number of glomeruli (less than
250) are examined. (Jones' silver stain, X200).
foci of segmental sclerosis with intracapillary foam cells and
prominence of overlying visceral epithelial cells. This is
representative of an early segmental sclerosing lesion in focal
segmental glomerulosclerosis (FSGS). There is also
surrounding mild interstitial fibrosis, and the glomerulus that
is sclerosed is mildly enlarged. Of note, significant
glomerular-size increase, even without segmental sclerosis, is
an indicator of possible unsampled or evolving FSGS. (Jones'
silver stain, X100).

More advanced lesions of FSGS are present in this biopsy,

with a central glomerulus showing global sclerosis, the
glomerulus on the left showing well-defined peripheral
The glomerular basement membrane is of normal thickness
segmental sclerosis, and the glomerulus on the right showing
without deposits in this case of minimal change disease. The
no lesions in this section. There is moderate interstitial fibrosis
visceral epithelial cells show diffuse effacement of foot
and tubular atrophy. The presence of globally sclerotic
processes. An area of microvillous transformation is also
glomeruli does not aid in the specific diagnosis of FSGS,
present, representing the irregular epithelial-cell surface that
because global sclerosis may occur nonspecifically related to
occurs in proteinuric states. Foot-process effacement is
other injury processes or aging. (Jones' silver stain, X100).
generally quite extensive in minimal change disease, although
the degree of foot-process effacement cannot be used to
definitively distinguish minimal change disease from
unsampled FSGS. (Transmission electron microscopy, X800).

Focal Segmental Glomerulosclerosis

Advanced segmental sclerotic lesions are present in these two

glomeruli, with increased mesangial matrix and obliteration of
capillaries and with more extensive lesion in the glomerulus
on the right. The lesions are typical of idiopathic FSGS. The
interstitium show moderate to severe fibrosis and tubular
atrophy. (Periodic acid-Schiff stain, X200).
In this biopsy, the segmental sclerotic lesion on the right with
FSGS is composed of obliteration of capillary lumens and
increased mesangial matrix. The remaining portion of the
glomerular tuft appears unremarkable, without basement
membrane changes or any apparent deposits. The visceral
epithelial cells overlying this early sclerotic lesion appear
activated. (Jones' silver stain, X400).
This glomerulus shows segmental sclerosis with hyalinosis,
typical of FSGS. Hyalin is defined as smooth, glassy-
appearing material, resulting from the insudation of plasma
proteins. It frequently occurs in sclerotic lesions, regardless of
primary origin, and is not of primary diagnostic significance.
It is frequently observed in cases of FSGS, whether primary or
secondary. (Jones' silver stain, X400).
Immunofluorescence studies in cases of FSGS may show
immunoglobulin (Ig) M in mesangial areas or in areas of
hyalinosis (smooth, globular staining on right). These may be
associated with small areas of electron density by electron
microscopy, although typical immune-complex densities are
not found. The IgM staining is thought to represent trapping in
areas of expanded mesangium and sclerosis.
(Immunofluorescence with anti-IgM, X200).
The mesangial matrix is mildly increased without deposits in
this case of FSGS. Endothelial cells are unremarkable, and
visceral epithelial cells show extensive blunting and
effacement of foot processes with early microvillous
transformation. Occasional vacuolization and blebbing is also
present in the visceral epithelial cells. No immune complexes
are present. (Transmission electron microscopy, X3,000).
Collapsing Glomerulopathy
Collapsing glomerulopathy is characterized by collapse of the
glomerular tuft with marked proliferation of overlying
glomerular visceral epithelial cells, often with prominent
protein droplets, as shown here. There is typically
accompanying disproportionate tubular injury in more
advanced cases, frequently with microcystic change. (Jones'
silver stain, X400).
The collapsing pattern in collapsing glomerulopathy is evident
here, with an accentuation of each lobule due to the collapse
of the tufts. There is also overlying glomerular visceral
epithelial cells. Occasional intercapillary foam cells are also
evident. The light microscopic appearance is similar in HIV-
associated nephropathy. Microcystic tubular injury is shown
on the edge of this slide. (Jones' silver stain, X400).

The sclerotic lesion here is sharply localized to the proximal

tubular pole, with adhesion and continuity of the capillary
loop to Bowman's capsule, and intercapillary foam cells
localized to this area, characteristic of the so-called tip lesion
variant of FSGS. (Jones' silver stain, X400).

C1q Nephropathy
In idiopathic collapsing glomerulopathy, the collapse of the
tufts is evident by electron microscopy, and there is foot
process effacement with extensive microvillus change. This is
associated with loss of differentiation markers of the
glomerular visceral epithelial cells. In idiopathic collapsing
glomerulopathy there are no reticular aggregates, in contrast to
their frequent presence in cases of HIV nephropathy.
(Transmission electron microscopy, X6000).

Tip Variant of FSGS

Glomeruli may show normal appearance, have varying

mesangial proliferation, or even segmental sclerosis by light
microscopy in C1q nephropathy. This glomerulus shows mild
mesangial hypercellularity with minimal increase in the
matrix. (Jones' silver stain, X200).

The localized sclerotic lesion that only involves the proximal

tubular pole of the glomerulus has been classified as the tip
lesion, with some evidence suggesting a better prognosis than
typical FSGS. As in minimal change disease and FSGS, there
are no immune complexes, and electron microscopy shows
extensive foot process effacement (not shown, see minimal
change disease). (Jones' silver stain, X200).
In this case of C1q nephropathy, well-defined segmental
sclerotic lesions with increased matrix and obliteration of
capillary lumens and adhesion to Bowman's capsule were
present. The uninvolved portion of the glomerular tuft shows a
mild to moderate increase in mesangial matrix and a minimal
increase in mesangial cellularity. There is mild interstitial
fibrosis. (Periodic acid-Schiff, X200).

Immunofluorescence shows mesangial or even paramesangial
staining for C1q in C1q nephropathy, typically with lesser
intensity staining for immunoglobulin (Ig) and C3. The
immunofluorescence findings in C1q nephropathy are crucial
in making the diagnosis and ruling out possible IgA
nephropathy. In this glomerulus, sharply defined mesangial
C1q was present, corresponding to electron-dense immune
complex-type deposits seen by electron microscopy (see Fig
4). (Immunofluorescence with anti-C1q, X200).
Electron microscopic studies in C1q nephropathy confirm
mesangial deposits underlying the basement membrane as it
traverses over the mesangial area. There are no reticular
aggregates present, a feature useful in distinguishing this from
possible lupus nephritis. (Transmission electron microscopy,
X3,000).
Membranous Gloemrulonephritis
Intact cortex with apparently normal glomeruli on low power
in early membranous glomerulonephritis (Jones' silver stain,
original magnification x100).
In this case of stage I membranous glomerulonephritis, the
capillary wall is slightly prominent and appears more rigid
than normal. However, deposits cannot be directly visualized
on this periodic acid-Schiff stain (original magnification
x400).
The thickened capillary wall shows numerous "holes" in
tangential sections, indicating deposits. (Deposits do not take
up the silver stain.) Well-developed spikes around the deposits
are not present in this early stage II membranous
glomerulonephritis, but segmental, small nubs of silver-
stained basement membrane material protruding from the
basement membrane contour on the epithelial side can be seen
(Jones' silver stain, original magnification x400)
High-power oil-immersion view of the markedly thickened
capillary wall in (A) stage II-III and (B) stage III membranous
glomerulonephritis. Well-developed spikes of basement
membrane silver-staining material protrude from the basement
membrane. In tangential sections, holes are seen, indicating
the presence of the silver-negative deposits. In stage III, some
of the deposits are completely surrounded by basement
membrane, and the basement membrane appears split in these
areas (Jones' silver stain, original magnification x1,000).

Diffuse coarsely granular capillary wall IgG deposits in stage

High-power oil-immersion view of the markedly thickened II-III membranous glomerulonephritis (immunofluorescence
capillary wall in (A) stage II-III and (B) stage III membranous with anti-IgG, original magnification x100).
glomerulonephritis. Well-developed spikes of basement
membrane silver-staining material protrude from the basement
membrane. In tangential sections, holes are seen, indicating
the presence of the silver-negative deposits. In stage III, some
of the deposits are completely surrounded by basement
membrane, and the basement membrane appears split in these
areas (Jones' silver stain, original magnification x1,000).

Capillary loops with diffuse, granular capillary wall IgG

deposits in stage II-III membranous glomerulonephritis
(immunofluorescence with anti-IgG, original magnification
x400).

Idiopathic membranous glomerulonephritis is a diagnosis of

exclusion. In this case of secondary membranous
glomerulonephritis, hepatitis B infection was the likely
underlying etiology. Morphological clues in this case
indicating that the membranous glomerulonephritis is
secondary rather than idiopathic, include mesangial expansion
and mesangial deposits (Jones' silver stain, original
magnification x200)

Small subepithelial dense deposits in early stage I

membranous glomerulonephritis. There is no surrounding
basement membrane reaction. Foot processes are extensively
effaced (transmission electron microscopy, original
magnification x10,500).

Diffuse finely granular capillary wall IgG deposits in stage I

membranous glomerulonephritis (immunofluorescence with
anti-IgG, original magnification x200).
 deposits, a feature of stage III membranous
glomerulonephritis, whereas most of the deposits still only
have basement membrane reaction around the side (stage II
lesion)(transmission electron microscopy, original
magnification x1,650).

Medium-sized dense deposits on the epithelial side of the

basement membrane (subepithelial) with occasional early
basement membrane reaction, late stage I membranous
glomerulonephritis (transmission electron microscopy,
original magnification x10,200).

Stage II membranous glomerulonephritis with medium-sized

subepithelial dense deposits and basement membrane reaction
around the sides of the deposits, which gives rise to the
"spike" appearance on Jones' silver stain (see Fig 4). Epithelial
cells show effaced foot processes. The endothelial cells show
normal fenestrae (transmission electron microscopy, original
magnification x1,650).

Stage II membranous glomerulonephritis with many

subepithelial electron dense deposits along the capillary loops.
Foot processes are effaced. There is basement membrane–like
material around the sides of the deposits, which gives rise to
the "spike" appearance on Jones' silver stain (see Fig
4)(transmission electron microscopy, original magnification
x1,650).

Stage III membranous glomerulonephritis with medium-sized

subepithelial dense deposits and basement membrane reaction
surrounding most of the deposits. In the center, a lucent area
partially replaces a deposit that is being resorbed. Bowman's
capsule and the parietal epithelium is on the far right.
(transmission electron microscopy, original magnification
x11,000).

Stage II-III membranous glomerulonephritis with thickened

capillary wall resulting from numerous medium to large
subepithelial dense deposits and basement membrane reaction.
Basement membrane–like material surrounds some of the
 Diffuse lobular simplification of glomeruli in
membranoproliferative glomerulonephritis type 1, caused by
extensive endocapillary proliferation (Jones' silver stain;
original magnification, x100).
Stage III-IV membranous glomerulonephritis with mostly
rarefied deposits or lucent areas instead of dense deposits,
with surrounding and overlying basement membrane reaction.
A few small, dense deposits immediately under the epithelium
overlying the lucent areas surrounded by basement membrane
reaction are present, indicating ongoing, new deposit
formation (transmission electron microscopy, original
magnification x7,200).

Extensive double contours of the glomerular basement

membranes, stained by silver, in membranoproliferative
glomerulonephritis type 1, caused by mesangial interposition
and new basement membrane formation in response to
subendothelial immune complex deposits. The deposits are
PAS positive and globular-to-sausage shaped (Jones' silver
stain; original magnification, x400).

Secondary membranous glomerulonephritis with numerous

subepithelial deposits (stage II) and mesangial deposits. In this
case, the likely underlying etiology was hepatitis B infection
(see Fig 5 above)(transmission electron microscopy, original
magnification x1,650).

Membranoproliferative Glomerulonephritis

Segmental, coarsely granular-to-globular or elongated

capillary wall IgG deposits in membranoproliferative
glomerulonephritis type 1 (immunofluorescence with anti-
IgG; original magnification, x200).
Segmental, irregular, coarsely granular, or elongated deposits
large subendothelial deposits molding under the glomerular
along the capillary wall and occasional mesangial IgG
basement membrane and occasional mesangial deposits are
deposits are typical of membranoproliferative
present (immunofluorescence with anti-C3; original
glomerulonephritis type 1 (immunofluorescence with anti-
magnification, x400)
IgG; original magnification, x200).

Membranoproliferative glomerulonephritis type 1. The

The subendothelial location of these segmental, irregular IgG marked endocapillary proliferation (proliferating endothelial
capillary wall deposits can be deduced by their smooth outer and mesangial cells) appears to occlude the capillary lumen.
contour, caused by molding against the glomerular basement Numerous large subendothelial and occasional mesangial-
membrane. These deposits are typical of dense immune complex-type deposits (bottom middle) are
membranoproliferative glomerulonephritis type 1 present (transmission electron microscopy; original
(immunofluorescence with anti-IgG; original magnification, x4,700).
magnification,x200).

Membranoproliferative glomerulonephritis type 1 with

In secondary forms of immune complex-mediated
multiple, large subendothelial deposits (transmission electron
membranoproliferative glomerulonephritis (such as those
microscopy; original magnification, x10,000).
caused by chronic infections), the deposits and proliferation
are commonly more focal and segmental than in idiopathic
membranoproliferative glomerulonephritis type 1.
Membranoproliferative glomerulonephritis type 1 with
multiple, small-to-medium subendothelial deposits
(transmission electron microscopy; original magnification,
x14,000).
Membranoproliferative glomerulonephritis type 1.
a small subendothelial deposit lies between the glomerular
basement membrane and an interposed mesangial cell,
extending from the mesangial area seen on the right. Between
the interposed mesangial cell, and the endothelium, new
basement membrane material is present (transmission electron
microscopy; original magnification, x6,300).
Although subepithelial hump-shaped deposits are
characteristic of acute postinfectious glomerulonephritis,
occasionally such deposits may be present in
membranoproliferative glomerulonephritis type 1, as shown in
this case, in addition to the typical subendothelial deposits
(original magnification, x16,000).
Dense Deposit Disease
Dense deposit disease is also called membranoproliferative
glomerulonephritis type 2 based on the similar light
microscopic findings in the two conditions. Mesangial
proliferation, double countours of the glomerular basement
membrane, and mesangial interposition are evident in this
figure. No obvious deposits, which typically appear pink on
this PAS-methenamine silver stain, are visualized. The
refractile, ribbon-like appearance of the basement membrane
is a clue to the correct diagnosis of dense deposit disease,
which is confirmed by immunoflurorescence and electron
microscopy (Jones' silver stain; original magnification, x400).
Dense deposit disease stains strongly for complement in an Fibrillary Glomerulonephritis
irregular, segmental capillary wall distribution, with
occasional mesangial staining. Immunoglobin staining is
typically absent, indicating there are no true immune complex-
type (ie, antibody-antigen) deposits (immunofluorescence with
anti-C3; original magnification, x200).

Fibrillary glomerulonephritis has varying appearances by light

Dense deposit disease also may show large, globular
mesangial staining for C3, in addition to the capillary wall
staining (immunofluorescence with anti-C3; original
magnification, x400).
microscopy, with mild to extensive mesangial proliferative
and membranoproliferative appearance being the most
common. In this case, there was a distinct
membranoproliferative and even nodular appearance (Jones
silver stain; original magnification x100).

Fibrillary glomerulonephritis may have varying degrees of

Dense deposit disease with dense transformation of the
glomerular basement membrane, endocapillary proliferation
and large, globular mesangial densities (transmission electron
micrograph; original magnification, x4600).
mesangial proliferation or membranoproliferative pattern by
light microscopy. In this case, there was moderate mesangial
proliferation and occasional basement membrane splitting.
Additional studies confirmed the diagnosis of fibrillary
glomerulonephritis with typical electron microscopy
appearance, negative Congo red stain, and IgG staining by
immunofluorescence (Jones silver stain; original
magnification x400). See other figures.

Dense deposit disease showing dense transformation of

virtually the entire width of the glomerular basement
membrane (transmission electron micrograph; original
magnification, x8000).
 In approximately one third of cases seen in our series of
fibrillary glomerulonephritis, crescents were present, as in this
case. In some of these, confluent deposits caused
immunofluorescence to have a pseudolinear appearance,
which could give rise to diagnostic confusion until electron
microscopy is examined (Jones silver stain; original
magnification x200).
Immunofluorescence studies in fibrillary glomerulonephritis
are striking and characteristic with smudgy positivity in
mesangial and capillary loop areas. The mesangial staining
most commonly is more extensive than the capillary loop
staining, and the typical smudginess allows suspicion of
fibrillary glomerulonephritis. The most common staining is
IgG, with IgG4 subtype typically being most prominent (anti-
IgG immunofluorescence; original magnification x400).
The diagnosis of fibrillary glomerulonephritis is ultimately
made by electron microscopy, which shows randomly
arranged fibrils in mesangial and capillary loop areas with an
intramembranous, subepithelial, and/or subendothelial
location. Negative Congo red stains are necessary to
specifically exclude the possibility of amyloid (transmission
electron microscopy; original magnification x25,625).
Higher power shows randomly oriented fibrils in the
mesangium and glomerular basement membrane in fibrillary
glomerulonephritis. These fibrils tend to be slightly larger than
those in amyloid, although there is some overlap so that fibril
size alone cannot be used to definitively distinguish this from
amyloid. A negative Congo red stain should be done to rule
out amyloid deposits (transmission electron microscopy;
original magnification x51,250).
Distinct subepithelial localization of fibrillary deposits in a
case of fibrillary glomerulonephritis. In this case,
immunofluorescence and light microscopic studies gave the
impression of a membranous glomerulonephritis, illustrating
the utility and need for electron microscopy to definitively
evaluate renal biopsies. The fibrils are randomly oriented and
somewhat larger than in amyloid, 12 to 15 nm, although there
is some overlap so that size alone cannot be used to
definitively distinguish this from amyloid deposits
(transmission electron microscopy; original magnification
x62,000).

High-power view of fibrils in fibrillary glomerulonephritis,
illustrating slightly coarser diameter than in amyloid. The
fibrils are randomly arranged in the loose background. A
negative Congo red stain is necessary to definitively rule out
amyloid deposits, although fibrillary glomerulonephritis can
be suspected from the characteristic immunofluorescence
microscopy and the slightly larger fibril size (transmission
electron microscopy; original magnification x98,000).
Immunoactoid Glomerulopathy
Immunotactoid glomerulopathy typically shows mesangial
proliferation or a membranoproliferative pattern by light
microscopy, as in this case. There is widespread splitting of
the glomerular basement membrane and increased mesangial
matrix, with thickened Bowman's capsule and adhesions of the
tuft to Bowman's capsule (Jones' silver stain, x 400).
Immunotactoid glomerulopathy shows positivity for IgG and
rarely other immunoglobulins, along with complement. The
positivity is in a segmental capillary loop distribution, along
with mesangial positivity, mirroring the distribution of
deposits by light microscopy. Deposits more typically are
polyclonal, although there may be predominance of one light
chain, as in this case, where there was predominant IgG kappa
staining, but with concomitant lambda staining (anti-kappa
antibody, x 400).
Immunotactoid glomerulopathy is defined, in our view, by the
presence of organized deposits by electron microscopy, which
show stacking in parallel arrays and/or microtubular
substructure. This morphology may be seen in immunotactoid
glomerulopathy, or be associated with paraproteins such as
cryoglobulin (see Cryoglobulinemic Glomerulonephritis
section). In this case there are massive mesangial and
subendothelial deposits with deposits organized in parallel
arrays, some cut longitudinally and some cut in cross-section.
The microtubules are quite large, close to 50 nm in diameter
(transmission electron microscopy, x 4,000).
Immunotactoid glomerulopathy deposits show organized
structure by electron microscopy, either organized in parallel
arrays, and/or with microtubular substructure. Some deposits
are cut in cross-section, clearly revealing the microtubular
substructure, whereas others, stacked in adjacent parallel
arrays, are cut longitudinally. These deposits permeate the
glomerular basement membrane; there is complete overlying
effacement of foot processes on the left (transmission electron
microscopy, x 9,500).
Postinfectious Glomerulopathy
 glomerulonephritis, with the prototype being poststreptococcal
glomerulonephritis (Jones' silver stain; original magnification
x400).

Glomeruli show diffuse hypercellularity due to mesangial and

endothelial cell increase and a large number of
polymorphonuclear neutrophils (PMNs). These light
microscopic findings are typical of diffuse proliferative acute
postinfectious glomerulonephritis (hematoxylin & eosin;
Crescents may occasionally be found in diffuse proliferative
original magnification x100).
acute postinfectious glomerulonephritis, particularly in those
patients who undergo renal biopsy when spontaneous
resolution does not occur. The crescent in this case has
ruptured Bowman's capsule, and there is an intense
lymphoplasmocytic interstitial infiltrate surrounding the
glomerulus (Jones' silver stain; original magnification x200).

Diffuse proliferative acute postinfectious glomerulonephritis

with numerous PMNs with PAS-positive cytoplasm and
endocapillary proliferation (periodic acid-Schiff; original
magnification x400).

Acute postinfectious glomerulonephritis by

immunofluorescence typically shows irregular capillary loop
deposits staining for IgG, seen here, or C3, seen in Figure 6
(immunofluorescence with anti-IgG; original magnification
x400).

The large number of PMNs typical of acute poststreptococcal

glomerulonephritis is evident in this high-power silver stain.
The glomerular basement membrane does not show splitting
or spikes. There is endocapillary proliferation, ie, proliferation
of endothelial and mesangial cells and infiltrating cells in
addition to filling and distending capillary loops. The large
number of PMNs is characteristic of postinfectious
The garland pattern of immune complexes due to large
subepithelial deposits in acute postinfectious
glomerulonephritis is shown (immunofluorescence with anti-
IgG; original magnification x400).

The scattered capillary wall granular deposits in acute

poststreptococcal glomerulonephritis also stain for
complement (immunofluorescence with antibody to C3; Hump- or dome-shaped deposits in acute postinfectious
original magnification x400). glomerulonephritis with extensive foot process effacement and
endocapillary proliferation (transmission electron micrograph;
original magnification x11,250).

Large, subepithelial, hump-like scattered deposits in acute

postinfectious glomerulonephritis. The deposits are irregularly
In this case of acute postinfectious glomerulonephritis, only
spaced and frequently mottled, and they sit on top of the
rare subepithelial deposits remain with occasional
basement membrane with little, if any, basement membrane
intramembranous deposits. At this later stage, the deposits
reaction (transmission electron micrograph; original
may be found only in the notch area, ie, where the basement
magnification x6,800).
membrane reflects over the mesangium. Such deposits may
indent the basement membrane as well as protrude above it, as
shown (transmission electron micrograph; original
magnification, x17,125).

IgA Nephropathy
 IgA nephropathy with moderate mesangial expansion with
IgA nephropathy with minimal increase in mesangial matrix
increased matrix and cells ([A] periodic acid-Schiff; [B] Jones'
and cells (normal is less than or equal to 3 cells/mesangial
silver stain; original magnification for each x200).
area). The diagnosis must rely on additional
immunofluorescence and electron microscopic studies ([A]
periodic acid-Schiff, original magnification x200; [B] Jones'
silver stain, original magnification x400).

IgA nephropathy with moderate mesangial expansion with

increased matrix and cells ([A] periodic acid-Schiff; [B] Jones'
silver stain; original magnification for each x200).
IgA nephropathy with minimal increase in mesangial matrix
and cells (normal is less than or equal to 3 cells/mesangial
area). The diagnosis must rely on additional
immunofluorescence and electron microscopic studies ([A]
periodic acid-Schiff, original magnification x200; [B] Jones'
silver stain, original magnification x400).

Increased mesangial cellularity and matrix in IgA nephropathy

(Jones' silver stain, original magnification x400).

Moderate diffuse mesangial expansion with increased matrix

and cellularity in IgA nephropathy (Jones' silver stain, original
magnification x100).
 IgA nephropathy may have superimposed segmental sclerosis
in addition to variable mesangial increase. (A) A small
peripheral sclerotic lesion with adhesion is present; (B) more
advanced segmental sclerosis is shown ([A] Jones' silver stain;
[B] periodic acid-Schiff; original magnification for each
x200).
IgA nephropathy may have superimposed segmental sclerosis
in addition to variable mesangial increase. (A) A small
peripheral sclerotic lesion with adhesion is present; (B) more
advanced segmental sclerosis is shown ([A] Jones' silver stain;
[B] periodic acid-Schiff; original magnification for each
x200).
The diagnosis of IgA nephropathy rests on the finding of
dominant or codominant IgA mesangial deposits, as shown
here. Staining may also be present for IgG and IgM, but not in
greater intensity than for IgA. C3 is also often present in the
mesangial areas, usually equal to or less than IgA staining
(anti-IgA immunofluorescence, original magnification x200).
Henoch-Schönlein purpura (HSP) also has mesangial IgA
deposits, and thus it appears morphologically like IgA
nephropathy. Clinicopathological correlation is required to
distinguish HSP from IgA nephropathy, but crescents, shown
here, are more frequent in biopsied HSP than in IgA
nephropathy (Jones's silver stain, original magnification
x100).
Mesangial electron dense deposits and increased mesangial
matrix and cellularity in IgA nephropathy (transmission
electron microscopy, original magnification x4,500).
Electron microscopic studies in diabetic nephropathy show
increased mesangial matrix and cellularity without deposits,
and a thickened glomerular basement membrane due to
marked widening of the lamina densa without deposits. Foot
processes frequently show effacement, most often subtotal.
Tubular basement membranes do not show deposits, an
important feature in excluding possible light chain deposition
disease in cases of nodular glomerulosclerosis. Occasional
fibrillar collagen may be present in sclerotic mesangial areas
in diabetes. (Transmission electron microscopy, original
magnification X3,000).

Immunofluorescence shows mesangial staining in WHO

Class IIb lupus nephritis, without peripheral capillary loop
deposits (immunofluorescence with anti-IgM; original
magnification x400).

Subendothelial deposits with wormy, short fibrillary

substructure, with slightly curvilinear fibrils often organized in
pairs, are illustrated. This type of substructure is suggestive of
a cryoglobulin causing the immune deposits, as was proven to
be the case in this patient (transmission electron microscopy;
original magnification x51,250).

Mesangial Lupus Nephritis

Electron-dense mesangial deposits are present in mesangial

lupus nephritis WHO Class IIb. There is paramesangial
extension of a deposit in the upper left, indicating incipient
progression to a proliferative form of lupus nephritis. Reticular
aggregates are also present in endothelial cell cytoplasm
(transmission electron microscopy; original magnification
x8,000).

Membranous Lupus Nephritis

Mesangial lupus nephritis (WHO Class IIb) shows mild

mesangial expansion by light microscopy, without evidence of
endocapillary proliferation. If mesangial immune complexes
are present but no mesangial increase is detected by light
microscopy, WHO Class IIa is diagnosed (PAS stain; original
magnification x200).

Membranous lupus nephritis, with diffuse holes and small

spikes visualized on the silver stain, along with mild
mesangial expansion with small areas of pink staining in
mesangial areas, indicative of mesangial deposits. Very mild
endocapillary increase of cells is also present, and occasional
subendothelial deposits were present by electron microscopy,
indicating a combination of lupus WHO Class V and very
early proliferative changes. This may be classified as lupus
WHO Class Vc, or if light microscopic changes warrant,
combined WHO Class IV and V (Jones silver stain; original
magnification x400).
Combined proliferative and membranous lupus nephritis
(WHO Class IV + V), evidenced by basement membrane
splitting, small spikes and holes in tangential sections, and a
small area of parietal epithelial cell proliferation and basement
membrane disruption, indicative of an early crescent
formation (Jones silver stain; original magnification x400).
Immunofluorescence in membranous lupus nephritis, WHO
Class Vb, with diffuse granular capillary wall and mesangial
positivity (immunofluorescence with anti-IgG; original
magnification x400).
Diffuse subepithelial dense deposits and lesser mesangial
deposits in this field in membranous lupus nephritis. Reticular
aggregates are also present in endothelial cell cytoplasm in
most cases of lupus nephritis (see Fig 9)(transmission electron
micrograph; original magnification x8000).
Combined proliferative and membranous form of lupus
nephritis, WHO Class IV and V, with massive subepithelial
and intramembranous deposits, frequent mesangial and
occasional subendothelial deposits and endocapillary
proliferation, distorting capillary loops (transmission electron
microscopy; original magnification x3,000).
Close-up of subepithelial deposits in lupus membranous
glomerulonephritis, with well developed spike formation and
early basement membrane formation overlying some deposits.
This case was classified as WHO Class Vb (mesangial
deposits not shown in this micrograph). Two endothelial cells
with well developed reticular aggregates are shown in the
middle of the field (transmission electron micrograph; original
magnification x10,000).
Lupus Nephritis: Proliferative Forms (WHO III, IV)
 Proliferative lupus nephritis is defined by endocapillary The segmental necrosis and proliferation with mild increase
proliferation due to subendothelial deposits, and may be focal in extracapillary cells, not reaching the level of a crescent, are
(less than 50% of glomeruli involved) or diffuse (greater than illustrated in this case of proliferative lupus nephritis (the
50% of glomeruli involved). The lesions are qualitatively process was focal in this biopsy, WHO III, which involves less
identical in focal and diffuse proliferative lupus nephritis than 50% of glomeruli). There is surrounding early interstitial
(WHO Class III and IV, respectively). The focal segmental fibrosis and lymphoplasmocytic infiltrate with thickening,
nature of proliferation in WHO Class III lupus nephritis is fibrosis, and rupture of Bowman's capsule in the glomerulus
illustrated. Some glomeruli appear to have only minor on the right (Jones' silver stain; original magnification x200).
mesangial expansion, whereas others have marked segmental
endocapillary proliferation and even necrosis. No
tubulointerstitial nephritis or fibrosis is seen in this biopsy.
There is also no sclerosis. Thus, activity is moderate, indicated
by proliferation and necrosis but relatively few crescents, and
chronicity is minimal, with absence of significant fibrosis or
sclerosis (Jones' silver stain; original magnification x100).

Diffuse proliferative lupus nephritis with segmental

endocapillary proliferation and eosinophilic subendothelial
sausage-shaped deposits visualized underlying the silver-
stained basement membrane segmentally. There is also an
early cellular crescent and rupture of Bowman's capsule
(Jones' silver stain; original magnification x400).

This biopsy shows findings typical of proliferative lupus,

which in this case was diffuse (WHO Class IV). One
glomerulus shows mild mesangial expansion and very
segmental endocapillary proliferation, whereas marked
segmental endocapillary proliferation and necrosis are present
in other glomeruli. The necrosis extends to the arteriole, and a
small cellular crescent has formed with the rupture of
Bowman's capsule and surrounding early fibrosis and
macrophages (Jones' silver stain; original magnification x200).

Diffuse proliferative lupus nephritis with segmental

endocapillary proliferation and eosinophilic subendothelial
sausage-shaped deposits visualized underlying the silver-
stained basement membrane segmentally. There is also an
early cellular crescent and rupture of Bowman's capsule
(Jones' silver stain; original magnification x400).
The segmental nature of proliferation in proliferative lupus
nephritis (WHO IV) is seen in this glomerulus, where half of
the tuft is distorted by marked endocapillary proliferation with
occasional infiltrating cells. Segmental areas of basement
membrane splitting and eosinophilic subendothelial deposits
and mesangial eosinophilic deposits are visualized (Jones'
silver stain; original magnification x400).
Extensive glomerular basement membrane alterations can be
seen corresponding to the extensive deposits in this case of
diffuse proliferative lupus nephritis (WHO Class IV). There is
segmental glomerular basement membrane splitting with
eosinophilic, large, sausage-shaped subendothelial deposits. In
other areas, bubbly holes can be seen in tangential sections of
the basement membrane, representing deposits that are
subepithelial (deposits do not take up the silver stain and are
outlined as holes in these cuts). Segmental endocapillary
proliferation and mesangial proliferation are also present
(Jones' silver stain; original magnification x600).
In this case of diffuse proliferative lupus nephritis (WHO
Class IV), there is moderate chronicity, evidenced by
moderate diffuse interstitial fibrosis, glomerulosclerosis, and
fibrocellular crescents. There is still remaining activity of this
proliferative process, evidenced by endocapillary proliferation
and tubulointerstitial lymphocytic infiltrate (periodic acid-
Schiff; original magnification x200).
Segmental capillary wall and mesangial deposits in
proliferative lupus nephritis are shown. In this case,
proliferation involved more than half of the glomeruli, ie,
diffuse proliferative lupus nephritis (WHO Class IV). Some of
the larger capillary wall deposits are sausage-shaped with
smooth outer contours, indicating they are subendothelial in
location. Other smaller granular deposits along the capillary
wall may correspond to smaller subepithelial deposits
(polyvalent antisera, immunofluorescence; original
magnification x200).
High-power view of diffuse proliferative lupus nephritis
(WHO Class IV) shows large, sausage-shaped capillary wall
deposits with smooth outer contours, indicative of
subendothelial deposits, and scattered small granular capillary
wall deposits, likely subepithelial deposits. Occasional
mesangial deposits are also present. In lupus nephritis,
staining of deposits with antisera to all three
immunoglobulins, IgG, IgM and IgA, is typical
(immunofluorescence with antibody to IgG; original
magnification x400).
Diffuse proliferative lupus nephritis (WHO Class IV) with
deposits that also stain for IgA (same case as in Figure 9).
Large, sausage-shaped capillary wall deposits with smooth
outer contours, indicating subendothelial location, are present
in addition to scattered granular capillary wall and mesangial
deposits. The segmental nature of deposits is apparent. A
similar staining pattern, but in less intensity, was present for
IgM, C3, and much weaker for C4 (immunofluorescence with
antisera to IgA; original magnification x400).
The endocapillary proliferation and subendothelial deposits
characteristic of proliferative lupus nephritis are illustrated in
this electron micrograph. Occasional small subepithelial, as
well as mesangial, deposits are present. The subendothelial
deposits range from small and sliver-shaped to very large,
with new basement membrane formation underlying the
deposits. The capillary loops are segmentally occluded by
proliferating endothelial and mesangial cells (transmission
electron micrograph; original magnification x8,000).
High-powered electron micrograph illustrates the
characteristic deposits of proliferative lupus nephritis. On the
right, a large subendothelial deposit and several smaller
subendothelial deposits are present. In addition,
intramembranous and subepithelial deposits with a prominent
spherule component (bottom right) are present. This type of
organized substructure may be present in lupus, and deposits
occasionally also show fingerprinting-type substructure. In
endothelial cells on the left, prominent reticular aggregates,
also known as tubuloreticular arrays, are present. These
organized arrays of cytoplasmic membranes are associated
with high levels of alpha-interferon, and are particularly
prominent in endothelial cells throughout the body in patients
with SLE or HIV. Foot processes are almost diffusely effaced,
and endothelial cells show moderate proliferation, partially
occluding the capillary lumen on the right (transmission
electron microscopy; original magnification x20,250).
Anti-GBM Antibody Mediated
Glomerulonephritis
Focal segmental fibrinoid necrosis is evident, with remaining
open glomeruli showing no proliferation or evidence of
immune complexes in this case of anti-GBM antibody-
mediated glomerulonephritis, a diagnosis confirmed by
immunofluorescence studies (Jones silver stain; original
magnification x100).
Early segmental fibrinoid necrosis with early cellular crescent
formation without endocapillary proliferation or evidence of
immune complexes in the remaining glomerular tuft. This
light microscopic finding is that of a pauci-immune
necrotizing glomerulonephritis, with a specific diagnosis of
anti-GBM antibody-mediated glomerulonephritis made by
immunofluorescence (Jones silver stain; original
magnification x400).
Smooth, linear staining of glomerular basement membranes
with antibody to IgG and crescent formation in the glomerulus
on the left, diagnostic findings of anti-GBM antibody-
mediated glomerulonephritis (immunofluorescence with anti-
IgG; original magnification x200).
Lung with linear staining along alveolar walls with antibody
for IgG in a patient with anti-GBM antibody-mediated
glomerulonephritis and pulmonary hemorrhage, typical of
Goodpasture's syndrome (immunofluorescence with anti-IgG;
original magnification x400).
Pauci-immune Necrotizing Crescenteric
Glomerulonephritis: Wegener’s
Granulomatosis/Microscopic Polyangiitis
Segmental fibrinoid necrosis with nuclear debris and
glomerular basement membrane disruption, typical of early
stage of pauci-immune crescentic glomerulonephritis,
diagnosed clinically as Wegener's granulomatosis in this case.
The morphological differential includes microscopic
polyangiitis and Wegener's granulomatosis, which cannot be
distinguished morphologically from the kidney biopsy.
Immunofluorescence studies are negative in both of these
diseases, and few if any, electron dense areas are found by
electron microscopy (Jones silver stain; original magnification
x400).
Well-developed cellular crescent with collapse of small
amount of remaining glomerular tuft with segmental fibrinoid
necrosis and extracapillary fibrin and necrosis in pauci-
immune crescentic glomerulonephritis, consistent with
Wegener's granulomatosis or microscopic polyangiitis.
Immunofluorescence studies were negative (Jones silver stain;
original magnification x400).
 and the specific diagnosis must be made by electron
microscopy. (Jones' Silver Stain, original magnification
X100).

Electron microscopy shows the absence of deposits along the

capillary wall in a case of pauci-immune crescentic
glomerulonephritis, consistent with Wegener's granulomatosis.
The glomerular basement membrane break, which is the unit
lesion leading to exudation of plasma proteins which
stimulates proliferation of parietal epithelial cells, leading to
crescent formation, is illustrated (transmission electron
microscopy; original magnification x8,000).
Interstitial foamy macrophages were previously thought to be
a sign indicative of Alport's Syndrome. However, it is now
recognized that this lesion is present in many conditions with
proteinuria, and electron microscopy is necessary to
specifically diagnose Alport's Syndrome. (Periodic Acid-
Schiff Stain, original magnification X100).

Open lung biopsy illustrating necrotizing granulomatous

inflammation and vasculitis, with negative cultures typical and
diagnostic of Wegener's granulomatosis (hematoxylin &
eosin; original magnification x100).
Alport’s Syndrome
In Alport's Syndrome, the glomerular basement membrane
shows irregular thinning and thickening with a lamellated
basket-weave appearance in the thickened area due to
extensive remodeling and injury of the basement membrane.
In cases with proteinuria, there may be moderate foot process
effacement. No immune complexes are present. (Transmission
electron microscopy, original magnification X6,000).

In stages of Alport's Syndrome where renal insufficiency is

manifest, glomerulosclerosis may be present in segmental or
global patterns with proportional interstitial fibrosis, as shown
in this case. No deposits are present by immunofluorescence,
By high power, the basket-weave, lamellated appearance of specifically allow definite prognostication. (Transmission
the glomerular basement membrane is readily apparent in this electron micrograph, original magnification X3,000).
case of Alport's Syndrome. There may also be interposition as
illustrated. In other areas, the basement membrane may show
only attenuation. (Transmission electron microscopy, original
magnification X10,000).

Thin Glomerular Basement Membranes

Close-up examination of thin basement membranes by

By light microscopy, no lesions are evident when thin
basement membranes are present. In some kindreds, increased
global obsolescence has been described, but this is a
nonspecific finding. In this patient with thin basement
membranes, no light microscopic lesion is present. (Jones'
Silver Stain, original magnification X200).
electron microscopy shows the marked attenuation of the
lamina densa, only severalfold the cross-sectional thickness of
the endothelial cell cytoplasm. Measurements from electron
microscopic prints are necessary to diagnose thin basement
membrane lesions. In this case, the thickness averaged
approximately 170 nm. There are no deposits and foot
processes are generally intact. (Transmission electron
microscopy, original magnification X9,000).
Diabetic Nephropathy

Diabetic nephropathy is characterized by light microscopy by

mesangial expansion, sometimes with nodule formation,
The diagnosis of thin basement membranes is made by mesangial hypercellularity, and a thickened glomerular
electron microscopy. There is diffuse attenuation of the basement membrane. In this case, there is diffuse mesangial
glomerular basement membrane, as illustrated here. In adults, hypercellularity and expansion with only small nodule
basement membrane thickness less than 250 nm is indicative formation. (Periodic acid-Schiff stain, original magnification
of thin basement membranes. However, processing and the X200).
age of the patient must be taken into consideration, because
basement membranes normally increase with maturational
growth. Thus, the diagnosis of thin basement membranes in
children must be made only after comparison for normal
standards in a given laboratory. The presence of thin basement
membranes is characteristic of so-called benign familial
hematuria, but can also be the only finding in early stages of
Alport's Syndrome, in female carriers of Alport's Syndrome,
and even at stages of established disease in some kindreds
with otherwise typical X-linked Alport's Syndrome. Thus, I
prefer to use the term thin basement membrane lesion, rather
than disease, because this morphologic finding does not
Diabetic nephropathy is one of the causes of nodular
glomerulosclerosis, illustrated here, with large nodules of
matrix within mesangial areas with lesser increase in
mesangial cellularity. The glomerular basement membrane is
thick without apparent deposits. (Periodic acid-Schiff stain,
original magnification X400).
Nodular glomerulosclerosis due to diabetic nephropathy may
present with large nodules of relatively acellular mesangial
matrix, as illustrated here. The glomerular basement
membrane is thickened, and both afferent and efferent
arterioles are hyalinized, in contrast to the hyalinization of the
afferent arteriole only in hypertension. (Periodic acid-Schiff
stain, original magnification X200).
There is diffuse mesangial matrix expansion and increased
mesangial hypercellularity and prominent glomerular
basement membranes in diabetic nephropathy, as shown here.
The basement membrane is uniformly thick without evident
deposits. (Periodic acid-Schiff stain, original magnification
X400).
The glomerular basement membrane is thickened without
evident deposits in diabetic nephropathy. The nodular
mesangial expansion has a lamellated appearance on this
silver stain, which is thought to be due to repeated injury with
mesangiolysis and subsequent increased matrix accumulation.
RBC fragments are present in the nodule, likely a consequence
of local microvascular inury. (Jones' silver stain, original
magnification X400).
Both afferent and efferent arterioles, shown here at the
vascular pole, are hyalinized in diabetic nephropathy. This
insudation of plasma proteins is due to endothelial injury. In
contrast to hypertensive lesions where only the afferent
arteriole is affected, there is injury to both afferent and
efferent arterioles in diabetic nephropathy. There is also
mesangial matrix expansion and prominent basement
membranes, and a focus of hyalin within the sclerotic area in
the glomerulus (top left). (Jones' silver stain, original
magnification X400).
Diabetic nephropathy may also show hyalin within Bowman's
capsule, the so-called capsular drop. This lesion is uncommon
and, although not entirely specific for diabetic nephropathy, is
distinctly unusual in other entities. The glomerulus shows
mesangial expansion, a small area of nodule formation, and
prominent basement membranes, all indicative of diabetic
nephropathy. (Periodic acid-Schiff stain, original
magnification X100).
This case shows nodular glomerulosclerosis and linear
accentuation of the glomerular basement membrane with IgG,
which is typical of diabetic nephropathy. There are no immune
complexes in diabetic nephropathy, although obviously
superimposed disease may occur (IgA nephropathy,
membranous glomerulonephritis, and thin basement
membrane lesion are particularly common as concurrent
glomerular lesions). It is also important to rule out light chain
deposition disease in cases of nodular glomerulosclerosis,
which may be done by examining k and l staining. (Anti-IgG
immunofluorescence, original magnification X400).
Thrombotic microangiopathy is a lesion seen in many
conditions, including hemolytic uremic syndrome, radiation
nephritis, toxicity related to various drugs, and hereditary
forms. The morphological lesions in these various conditions
are the same. The lesion consists of fibrin thrombi within
glomeruli, which may extend to arterioles. In this patient with
hemolytic uremic syndrome, the thrombotic microangiopathy
was confined to glomeruli, with extensive fibrin thrombi and
platelet plugs filling up the capillary loops. (Jones' silver stain,
original magnification X200).

Electron microscopic studies in diabetic nephropathy show

In this case of thrombotic microangiopathy, the fibrin thrombi
increased mesangial matrix and cellularity without deposits,
extend from the glomerular capillary loop to the arteriolar
and a thickened glomerular basement membrane due to
vascular pole, a finding associated with worse prognosis. If the
marked widening of the lamina densa without deposits. Foot
vascular lesions are extensive, cortical necrosis may even
processes frequently show effacement, most often subtotal.
ensue. (Jones' silver stain, original magnification X200).
Tubular basement membranes do not show deposits, an
important feature in excluding possible light chain deposition
disease in cases of nodular glomerulosclerosis. Occasional
fibrillar collagen may be present in sclerotic mesangial areas
in diabetes. (Transmission electron microscopy, original
magnification X3,000).

Thrombotic Microangiopathy

In chronic stages of injury after thrombotic microangiopathy,

organization of the injury may result in a split appearance of
the basement membrane, simulating a membranoproliferative-
like lesion. However, no immune complexes are present, and
the differential diagnosis is easily resolved by ancillary
immunofluorescence and electron microscopic studies. (Jones'
silver stain, original magnification X200).
In severe cases of thrombotic microangiopathy, cortical
necrosis may occur, especially when lesions extend to larger
vessels, as in this case. Both tubules and glomeruli are
necrotic, with fibrin filling the glomerulus and an interlobular
vessel, with early signs of chronic injury with intimal fibrosis
and fibrin occluding the lumen. (Jones' silver stain, original
magnification X200).
Fibrin tactoids can also be visualized by electron microscopy
in cases of thrombotic microangiopathy, along with
endothelial cell swelling and expansion of the lamina rara
interna. (Transmission electron microscopy, original
magnification X6,000).
In thrombotic microangiopathy, no deposits are seen by
electron microscopy or immunofluorescence. In more chronic
stages, new basement membrane may be formed after the
endothelial injury and early interposition with expansion of
the lamina rara interna can occur, as illustrated in this case.
(Transmission electron microscopy, original magnification
X3,000).
Progressive Systemic Sclerosis
In progressive systemic sclerosis, many features overlap with
those seen in malignant hypertension, with fibrinoid necrosis
of vessels. There may also be fibrin thrombi extending into
glomeruli, overlapping with the lesions typical of thrombotic
microangiopathy. However, in typical progressive systemic
sclerosis, injury often extends to larger vessels, contrasting the
typical predominance of glomerular involvement in
thrombotic microangiopathy. An uninvolved interlobular
artery and an interlobular artery with extensive fibrinoid
necrosis are shown in longitudinal section, with only ischemic
changes in glomeruli. (Jones' silver stain, original
magnification X200).
The artery shows early organization with "onion skin" change
caused by lamellation and mucoid change with swelling of the
intimal layer, with corrugation of the glomerular basement
membrane, in this case of progressive systemic sclerosis.
(Jones' silver stain, original magnification X200).
In early stages of progressive systemic sclerosis, mucoid
changes in the vessel wall predominate, with swollen
endothelium and a mucoid appearance of the subintima,
frequently with red blood cell fragments, as seen here. (Jones'
silver stain, original magnification X400).
Hypertensive nephrosclerosis is characterized by medial
thickening and intimal fibrosis of medium-sized and larger
vessels, arteriolar thickening, and hyalinosis, frequently
associated with global glomerulosclerosis with obsolescence
of glomeruli, as shown here. There is proportional
tubulointerstitial fibrosis. (Periodic acid-Schiff stain, original
magnification X100).

In the more chronic stage of progressive systemic sclerosis,

fibrous organization of the intimal injury results in a
lamellated "onion skin" appearance of arteries. (Periodic acid
Schiff, original magnification X400).

Hyalinosis is evident in the arteriole and interlobular artery in

hypertensive nephrosclerosis, along with mild medial
thickening caused by both hypertrophy and hyperplasia of
vascular smooth muscle cells. The hyalin material is the result
of insudation of plasma proteins, and is pink and glassy-
smooth in appearance (ie, hyalin). (Periodic acid-Schiff stain,
original magnification X200).

The glomeruli show evidence of endothelial injury and

ischemia, visualized by corrugation and expansion of the
lamina rara interna in this case of progressive systemic
sclerosis. (Transmission electron microscopy, original
magnification X3,000).

Hypertensive Nephrosclerosis
 Intimal fibrosis as well as medial thickening is evident in this
artery in a patient with hypertensive nephrosclerosis. (Periodic
acid-Schiff stain, original magnification X200).

Malignant Hypertension

The glomeruli in malignant or accelerated hypertension show

only ischemic change, seen here as extensive corrugation of
the glomerular basement membrane with expanded lamina
rara interna. (Transmission electron microscopy, original
magnification X8,000).

In malignant hypertension, also called accelerated Acute Tubular Necrosis

hypertension, there are often underlying changes as seen in
hypertensive nephrosclerosis, with superimposed fibrinoid
necrosis of the vessel wall. In this vessel, there is also fibrin
within the vessel wall, as a consequence of the necrosis.
Glomeruli show only ischemic changes. (Jones' silver stain,
original magnification X100).

Acute tubular necrosis may be manifest only by regenerating

flattened tubular epithelium without frank necrosis of
individual tubular cells, as shown in some tubules to the right
of the glomerulus, by bleebbing and individual cell
degenration (top left), or by frank necrosis ( middle). There is
minimal accompanying interstitial infiltrate (periodic acid
Schiff stain, x 100).
Fibrinoid necrosis of the vessel wall with pink, amorphous
fibrinoid material is present, with activated endothelial cells
and inflammatory cells in this artery in a patient with
malignant hypertension. There is also underlying medial
thickening of the vessel wall, indicative of preexisting
hypertensive injury. (Jones' silver stain, original magnification
X200).

There may also be degeneration and frank necrosis of

individual cells or tubular segments in acute tubular necrosis,
or flattened, regenerating type epithelium with degenerated
cells in the lumen (middle left) (hematoxylin and eosin, x
200).
Acute tubular necrosis is manifest by vacuolated cells and
sloughed, necrotic cells in tubular lumina, with some tubules
lined by flattened epithelium and some showing frank necrosis
(periodic acid Schiff stain, x 400).
Cortical Necrosis
Cortical necrosis is distinguished from acute tubular necrosis
in that glomeruli as well as tubules show frank necrosis. It
most often has a vascular occlusive etiology. Coagulative
necrosis is widespread in this transplant biopsy and is manifest
by small, pyknotic nuclei and ghost-like outlines of cells,
characteristic of coagulative necrosis (periodic acid Schiff,
x400).
Cortical necrosis with tubular necrosis and glomerular
necrosis. The glomerular basement membrane is still
visualized, but there are no viable nuclei in the glomerulus,
and surrounding tubules show frank necrosis, as do the
adjacent arterioles (Jones' silver stain, x400).
Cortical necrosis with widespread frank tubular necrosis with
no nuclei discernible in tubules and ghost-like outlines of
cells, characteristic of coagulative necrosis (periodic acid
Schiff, x200).
Cortical necrosis with widespread frank tubular necrosis with
no nuclei discernible in most tubules and ghost-like outlines of
cells, characteristic of coagulative necrosis. There are also
pyknotic nuclei and karryorhexis, characteristic of coagulative
necrosis (periodic acid Schiff, x400).
Acute Pyelonephritis
Acute pyelonephritis is diagnosed by intratubular aggregations
of polymorphonuclear neutrophils (PMNs). There may be
surrounding interstitial inflammation with a mixture of PMNs,
lymphocytes, and plasma cells, but the predominant
inflammation is within the tubules. (Jones' Silver Stain,
original magnification X200).

Glomerular scarring may be present in a focal and segmental

More extensive intratubular polymorphonuclear neutrophils
(PMNs) are present in this case of acute pyelonephritis. The
PMNs are easily recognizable by their multilobed irregular
nuclei. There is associated tubular degeneration and necrosis,
but only minimal interstitial changes. (Jones' Silver Stain,
original magnification X200).
pattern in chronic pyelonephritis/reflux nephropathy. Signs
suggestive of chronic pyelonephritis or reflux nephropathy as
the underlying etiology include periglomerular scarring
surrounding relatively intact glomeruli and thickened
Bowman's capsule. Glomerular enlargement may be present in
this form of secondary focal segmental glomerulosclerosis
(FSGS), as it is in primary FSGS. The pattern of
tubulointerstitial scarring and the regional, geographic pattern
of scarring (see above) are suggestive of the underlying
etiology. (Jones Silver Stain, original magnification X120).

Chronic Pyelonephritis

Small foci of acute inflammation, ie, polymorphonuclear

Chronic pyelonephritis is suggested when tubulointerstitial
fibrosis and glomerular scarring are present in a so-called
geographic pattern. This refers to irregular zones of scarring,
with intervening preserved areas, fitting together like jigsaw
pieces or like a map of countries bordering on each other.
There is often disproportionate tubulointerstitial inflammation,
and there may be foci of polymorphonuclear neutrophils
(PMNs) within tubules. (Jones' Silver Stain, original
magnification X100).
neutrophils (PMNs), within tubules in a setting of
tubulointerstitial scarring and glomerulosclerosis are
suggestive of chronic pyelonephritis as the underlying
etiology. In this case, degenerated cells and PMNs are present
in the tubule, with disproportionate interstitial chronic
inflammation, suggestive of chronic pyelonephritis with a
(sub)acute component (Periodic Acid-Schiff Stain, original
magnification X400).
In chronic pyelonephritis, the glomerular changes are
Eosinophils are frequently prominent in cases of acute
nonspecific. Secondary focal segmental glomerulosclerosis
interstitial nephritis because of drug-induced hypersensitivity
(FSGS) is often present, with foot process effacement without
reactions. Eosinophils are recognizable by the brightly
immune deposits by immunofluorescence and electron
eosinophilic granular cytoplasm on hematoxylin and eosin
microscopy. As illustrated here, foot process effacement is
stains, and their bilobed nuclei. There is also associated
often less extensive than in primary FSGS, although the
interstitial edema. (Hematoxylin and eosin, original
overlap prevents this finding from being a definitive
magnification X400).
diagnostic criterion. (Transmission electron microscopy,
original magnification X3,000).

Acute Interstitial Nephritis

There is edema in addition to preexisting mild

tubulointerstitial fibrosis in this case of acute interstitial
nephritis caused by drug-induced hypersensitivity. There is a
prominent interstitial eosinophilic component, in addition to
In acute interstitial nephritis, there is edema associated with lymphocytes and plasma cells. (Hematoxylin and eosin,
an interstitial lymphoplasmocytic infiltrate. There are original magnification X200).
numerous causes for acute interstitial nephritis, including
toxins, infections (especially viral), and most commonly in
renal biopsy practice, drug-induced hypersensitivity reactions. Acute Rejection, Type I (Interstitial)
The glomeruli are uninvolved, unless there is an associated
minimal change disease-type injury, most often seen with
drug-induced acute interstitial nephritis caused by nonsteroidal
antiinflammatory drugs. (Jones' silver stain, original
magnification X100).
Tubulitis, ie, infiltration of tubular epithelium by lymphocytes,
is the hallmark of type I interstitial acute rejection. Different
classifications have been put forth for diagnosis of acute
rejection. Among the most widely used are Banff, most
recently revised in 1997 (published in Kidney International
1999), and CCTT (published in the Journal of the American
Society of Nephrology 1998). The lower threshold for
rejection by CCTT criteria is 5% of non-scarred parenchyma
involved with tubulointerstitial lymphoplasmacytic infiltrate,
with tubulitis in at least three tubules, with accompanying
tubular injury, lymphocyte activation, and/or edema (at least 2
of these latter 3). In this biopsy, there is tubular injury, edema,
and multiple lymphocytes infiltrating under the glomerular
basement membrane. (Jones' Silver Stain, original
magnification X400). There is moderate edema and mild to moderate diffuse
interstitial lymphoplasmacytic infiltrate with destruction of
one tubular profile by infiltrating lymphocytes, with
degenerated tubular epithelial cells and apoptotic cells in the
lumen (left). Additional tubules show infiltration by
lymphocytes, ie, tubulitis. The constellation of these findings
is indicative of type I acute rejection. (Periodic Acid-Schiff,
original magnification X100).

Moderate interstitial lymphoplasmacytic infiltrate is present

with partial destruction of several tubules by infiltrating
lymphocytes, ie, tubulitis. The extent of this process was
sufficient to warrant a diagnosis of type I acute rejection.
Distinguishing tubulitis from lymphocytes in the interstitium
may be difficult on H&E sections, and a PAS or silver stain is
useful in demonstrating that tubulitis is present. (H&E,
original magnification X200). There is intense, severe interstitial lymphoplasmacytic
infiltrate that has nearly obliterated the underlying tubules.
There is extensive tubulitis. Changes of this severity are not
commonly seen in patients taking cyclosporine. When there is
extensive, nodular, expansive lymphoplasmacytic infiltrate,
atypia, and serpiginous necrosis, the alternative diagnosis of
posttransplant lymphoproliferative disorder should be
considered. In this case, there are only occasional plasma cells
and no nodular appearance, and the findings were those of
severe type I acute rejection in a teenage patient who stopped
taking antirejection medication. (Periodic Acid-Schiff, original
magnification X100).

Acute Rejection, Type II (Vascular)

There is marked tubulointerstitial lymphoplasmacytic infiltrate

and numerous lymphocytes infiltrating tubules, ie, tubulitis, in
this case of moderately severe type I acute rejection. (Jones'
Silver Stain, original magnification X200).
Acute vascular rejection is diagnosed by endothelialitis, ie,
lymphocytes infiltrating under the endothelium. It often is
There is severe subendothelial and transmural lymphocytic
present in conjunction with acute type I (interstitial) rejection,
infiltrate in this medium size artery, superimposed on changes
but may occur without concurrent interstitial rejection. It is
of chronic rejection, manifest by interstitial fibrosis and
thought that humoral mechanisms are pivotal in mediating
glomerulosclerosis and early transplant glomerulopathy. This
vascular-type rejection. The biopsy shows minimal finding may be present in transplant nephrectomies when
subendothelial lymphocytic infiltrate, diagnostic of type II immunosuppression has been tapered before graft removal, as
vascular rejection. (Periodic Acid-Schiff, original
in this case. (Jones' Silver Stain, original magnification X100).
magnification X100).

Acute Rejection, Type III

There is significant endothelialitis with mononuclear cells

underneath the endothelium of this large artery, indicative of
endothelialitis and type II acute vascular rejection.
(Hematoxylin and eosin, original magnification X200).
There is hyalinosis of the bottom interlobular artery and
necrosis with subendothelial lymphocytic infiltrate in the top
artery, indicative of type III acute vascular rejection. (Periodic
Acid-Schiff, original magnification X200).

Chronic Transplant Glomerulopathy

There is endothelial swelling and lymphocytic subendothelial

infiltration in this medium size artery, indicative of
endothelialitis (type II acute vascular rejection). (Periodic
Acid-Schiff, original magnification X200).
 Chronic transplant glomerulopathy may manifest as focal and
segmental glomerulosclerosis, as illustrated here. It frequently
occurs on a background of chronic transplant nephropathy and
findings of chronic rejection, evidenced by interstitial fibrosis
and vascular intimal fibrosis. (Periodic Acid-Schiff, original
magnification X100).

Glomerular basement membrane splitting with so-called

"mesangial" interposition is illustrated in this case of chronic
transplant glomerulopathy. Some of the interposed cells are
actually macrophages by immunophenotyping. (Jones' Silver
Stain, original magnification X1,000).

Chronic transplant glomerulopathy is manifest by light

microscopy by extensive glomerular basement membrane
splitting. Typically, there is less endocapillary proliferation
than in an immune complex mediated membranoproliferative
glomerulonephritis, which can easily be excluded by lack of
immune complexes by immunofluorescence and electron
microscopy. (Jones' Silver Stain, original magnification
X400).

Chronic transplant glomerulopathy is thought to be due to

chronic endothelial injury with resulting increased lucency of
the lamina rara interna and occasional interposition, without
any immune complexes, as shown in this electron micrograph.
(Transmission electron microscopy, original magnification
X3,000).

In chronic transplant glomerulopathy, there may be segmental

sclerosis and even hyalinosis in addition to glomerular
basement membrane splitting. (Jones' Silver Stain, original
magnification X1,000).