human kidneys serve to convert more than 1700 liters of blood
per day into about 1 liter of a highly specialized concentrated
fluid called urine.
Slide 4
The kidney excretes the waste products of metabolism, precisely
regulates the body's concentration of water and salt, maintains the
appropriate acid balance of plasma, and serves as an endocrine
organ, secreting such hormones as erythropoietin, renin, and
prostaglandins
Slide 5
Each human adult kidney weighs about 150 gm. The ureter enters
the kidney at the hilum, it dilates into a funnel-shaped cavity,
the pelvis, from which derive two or three main branches, the major
calyces; each of these subdivides again into three or four minor
calyces. There are about 12 minor calyces in the human kidney.
Slide 6
On the cut surface, the kidney is made up of a cortex and a
medulla, the former 1.2 to 1.5 cm in thickness. The medulla
consists of renal pyramids, the apices of which are called
papillae, each related to a calyx. Cortical tissue extends into
spaces between adjacent pyramids as the renal columns of
Bertin.
Slide 7
From the standpoint of its diseases, the kidney can be divided
into four components: blood vessels, glomeruli, tubules, and
interstitium.
Slide 8
The kidney is richly supplied by blood vessels, and although
both kidneys make up only 0.5% of the total body weight, they
receive about 25% of the cardiac output. The cortex is by far the
most richly vascularized part of the kidney, receiving 90% of the
total renal blood supply.
Slide 9
The main renal artery divides into anterior and posterior
sections at the hilum. From these, interlobar arteries emerge,
course between lobes, and give rise to the arcuate arteries, which
arch between cortex and medulla, in turn giving rise to the
interlobular arteries.
Slide 10
From the interlobular arteries, afferent arterioles enter the
glomerular tuft, where they progressively subdivide into 20 to 40
capillary loops arranged in several units or lobules
architecturally centered by a supporting mesangial stalk. Capillary
loops merge to exit from the glomerulus as efferent arterioles
Slide 11
In general, efferent arterioles from superficial nephrons form
a rich vascular network that encircles cortical tubules
(peritubular vascular network), and deeper juxtamedullary glomeruli
give rise to the vasa recta, which descend as straight vessels to
supply the outer and inner medulla.
Slide 12
These descending arterial vasa recta then make several loops in
the inner medulla and ascend as the venous vasa recta. The anatomy
of renal vessels has several important implications
Slide 13
First, because the arteries are largely end-arteries, occlusion
of any branch usually results in infarction of the specific area it
supplies Second,the blood in the capillary loops in the medulla has
a remarkably low level of oxygenation. Thus, minor interference
with the blood supply of the medulla may result in medullary
necrosis from ischemia
Slide 14
Glomerular disease that interferes with blood flow through the
glomerular capillaries has profound effects on the tubules, within
both the cortex and the medulla, because all tubular capillary beds
are derived from the efferent arteriole s.
Slide 15
Slide 16
Glomeruli
Slide 17
Slide 18
The glomerulus consists of an anastomosing network of
capillaries lined by fenestrated endothelium invested by two layers
of epithelium
Slide 19
The glomerular capillary wall is the filtering membrane and
consists of the following structures. A thin layer of fenestrated
endothelial cells, each fenestrum being about 70 to 100 nm in
diameter.
Slide 20
A glomerular basement membrane (GBM) with a thick
electron-dense central layer, the lamina densa, and thinner
electron-lucent peripheral layers, the lamina rara interna and
lamina rara externa.
Slide 21
The GBM consists of collagen (mostly type IV), laminin,
polyanionic proteoglycans (mostly heparan sulfate), fibronectin,
entactin, and several other glycoproteins. Type IV collagen forms a
network suprastructure to which other glycoproteins attach.
Slide 22
The building block (monomer) of this network is a
triple-helical molecule made up of three - chains, composed of one
or more of six types of -chains ( 1 to 6 or COL4A1 to COL4A6), the
most common consisting of 1, 2, 1
Slide 23
Slide 24
These biochemical determinants are critical to understanding
glomerular diseases. For example,the antigens in the NC1 domain are
the targets of antibodies in anti-GBM nephritis; genetic defects in
the -chains underlie some forms of hereditary nephritis; and the
acidic porous nature of the GBM determines its permeability
characteristics.
Slide 25
The visceral epithelial cells (podocytes), are structurally
complex cells that possess interdigitating processes embedded in
and adherent to the lamina rara externa of the basement membrane.
Adjacent foot processes (pedicels) are separated by 20- to
30-nm-wide filtration slits, which are bridged by a thin
diaphragm.
Slide 26
The entire glomerular tuft is supported by mesangial cells
lying between the capillaries. Basement membrane-like mesangial
matrix forms a meshwork through which the mesangial cells are
centered. These cells, of mesenchymal origin, are contractile,
phagocytic, and capable of proliferation, of laying down both
matrix and collagen, and of secreting a number of biologically
active mediators.
Slide 27
glomerular barrier function, discriminates among various
protein molecules, depending on their size (the larger, the less
permeable) and charge (the more cationic, the more permeable).
Slide 28
This size- and charge-dependent barrier function is accounted
for by the complex structure of the capillary wall, the collagenous
porous and charged structure of the GBM, and the many anionic
moieties present within the wall, including the acidic
proteoglycans of the GBM and the sialoglycoproteins of epithelial
and endothelial cell coats.
Slide 29
The charge-dependent restriction is important in the virtually
complete exclusion of albumin from the filtrate, because albumin is
an anionic molecule of a pI 4.5.
Slide 30
Tubules
Slide 31
The proximal tubule is particularly vulnerable to ischemic
damage. Furthermore, toxins are frequently reabsorbed by the
proximal tubule, rendering it also susceptible to chemical
injury
Slide 32
Interstitium
Slide 33
Any obvious expansion of the cortical interstitium is usually
abnormal; this expansion can be due to edema or infiltration by
acute inflammatory cells, as in acute interstitial diseases, or it
may be caused by accumulation of chronic inflammatory cells and
fibrous tissue, as in chronic interstitial diseases.
Slide 34
Renal diseases are responsible for a great deal of morbidity
but, fortunately, are not equally major causes of mortality.
Slide 35
approximately 70,000 deaths are attributed yearly to renal
disease in the United States, in contrast to about 700,000 to heart
disease, 550,000 to cancer, and 170,000 to stroke.
Slide 36
Millions of people are affected annually by nonfatal kidney
diseases, most notably infections of the kidney or lower urinary
tract, kidney stones, and urinary obstruction.
Slide 37
Twenty percent of all women suffer from infection of the
urinary tract or kidney at some time in their lives, and as many as
5% of the U.S.
Slide 38
dialysis and transplantation keep many patients alive who would
formerly have died of renal failure, adding to the pool of renal
morbidity. The cost of such programs now exceeds several billion
dollars annually
Slide 39
Diseases of the kidney are as complex as its structure, but
their study is facilitated by dividing them into those that affect
the four basic morphologic components: glomeruli, tubules,
interstitium, and blood vessels.
Slide 40
Azotemia is a biochemical abnormality that refers to an
elevation of the blood urea nitrogen (BUN) and creatinine levels
and is related largely to a decreased glomerular filtration rate
(GFR).
Slide 41
When azotemia becomes associated with a constellation of
clinical signs and symptoms and biochemical abnormalities, it is
termed uremia.
Slide 42
Slide 43
clinical presentations Of Renal Disease
Slide 44
1-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.
Slide 45
2-The nephrotic syndrome is characterized by heavy proteinuria
(more than 3.5 gm/day), hypoalbuminemia, severe edema,
hyperlipidemia, and lipiduria (lipid in the urine).
Slide 46
3- Asymptomatic hematuria or proteinuria, or a combination of
these two, is usually a manifestation of subtle or mild glomerular
abnormalities.
Slide 47
4-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.
Slide 48
5-Chronic renal failure, characterized by prolonged symptoms
and signs of uremia, is the end result of all chronic renal
parenchymal diseases.
Slide 49
6-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).
Slide 50
7-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.
Slide 51
8-Nephrolithiasis (renal stone) is manifested by renal colic,
hematuria, and recurrent stone formation.
Slide 52
9-Urinary tract obstruction and 10-renal tumors represent
specific anatomic lesions with often varied clinical
manifestations.
Slide 53
normal renal function to symptomatic chronic renal failure
progresses through four stages that merge into one another.
Slide 54
1-In diminished renal reserve, the GFR is about 50% of normal.
Serum BUN and creatinine values are normal, and the patients are
asymptomatic. However, they are more susceptible to developing
azotemia with an additional renal insult.
Slide 55
2-In renal insufficiency, the GFR is 20% to 50% of normal.
Azotemia appears, usually associated with anemia and hypertension.
Polyuria and nocturia can occur as a result of decreased
concentrating ability. Sudden stress (e.g., with nephrotoxins) may
precipitate uremia.
Slide 56
3-In renal failure, the GFR is less than 20% to 25% of normal.
The kidneys cannot regulate volume and solute composition, and
patients develop edema, metabolic acidosis, and hypocalcemia. Overt
uremia may ensue, with neurologic, gastrointestinal, and
cardiovascular complications.
Slide 57
4-In end-stage renal disease, the GFR is less than 5% of
normal; this is the terminal stage of uremia.
Slide 58
Congenital Anomalies
Slide 59
About 10% of all people are born with potentially significant
malformations of the urinary system. Renal dysplasias and
hypoplasias account for 20% of chronic renal failure in
children.
Slide 60
Autosomal-dominant polycystic kidney disease, a congenital
anomaly that becomes apparent in adults, is responsible for about
10% of chronic renal failure in humans.
Slide 61
Agenesis of the Kidney Hypoplasia Ectopic Kidneys Horseshoe
Kidneys
Slide 62
Pathology
Slide 63
Glomerular Diseases
Slide 64
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
Slide 65
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
Slide 66
HISTOLOGIC ALTERATIONS
Slide 67
Hypercellularity. Basement Membrane Thickening. Hyalinization
and Sclerosis.
Slide 68
The histologic changes can be further subdivided into diffuse,
involving all glomeruli; global, involving the entire glomerulus;
focal, involving only a proportion of the glomeruli; segmental,
affecting a part of each glomerulus; and mesangial, affecting
predominantly the mesangial region. These terms are sometimes
appended to the histologic classifications.
Two forms of antibody- associated injury have been
established:
Slide 73
1) injury by antibodies reacting in situ within the glomerulus,
either with insoluble fixed (intrinsic) glomerular antigens or with
molecules planted within the glomerulus
Slide 74
2) injury resulting from deposition of circulating
antigen-antibody complexes in the glomerulus.
Slide 75
In Situ Immune Complex Deposition In this form of injury,
antibodies react directly with intrinsic tissue antigen, or
antigens "planted" in the glomerulus from the circulation. in human
disease: antiglomerular basement membrane (anti-GBM)
antibody-induced nephritis and Heymann nephritis.
Slide 76
The injected antibodies bind along the entire length of the
GBM, resulting in a diffuse linear pattern of staining for the
antibodies by immunofluorescent techniques
Slide 77
(Goodpasture syndrome). The GBM antigen that is responsible for
classic anti-GBM antibody-induced nephritis and Goodpasture
syndrome is a component of the non-collagenous domain (NC1) of the
3 -chain of collagen type IV
Slide 78
Antibodies Against Planted Antigens Antibodies can react in
situ with antigens that are not normally present in the glomerulus
but are "planted" there
Slide 79
Circulating Immune Complex Nephritis In this type of nephritis,
glomerular injury is caused by the trapping of circulating
antigen-antibody complexes within glomeruli. The antibodies have no
immunologic specificity for glomerular constituents, and the
complexes localize within the glomeruli because of their
physicochemical properties and the hemodynamic factors peculiar to
the glomerulus
Slide 80
The antigens that trigger the formation of circulating immune
complexes may be of endogenous origin, as in the glomerulonephritis
associated with SLE
Slide 81
or they may be exogenous, as is likely in the
glomerulonephritis that follows certain infections. Microbial
antigens that are implicated include bacterial products
(streptococci), the surface antigen of hepatitis B virus (HBsAg),
hepatitis C virus antigen, and antigens of Treponema pallidum,
Plasmodium falciparum, and several viruses.
Slide 82
Some tumor antigens are also thought to cause immune
complex-mediated nephritis. In many cases, the inciting antigen is
unknown.
Slide 83
Electron microscopy reveals the immune complexes as
electron-dense deposits that lie in the mesangium, between the
endothelial cells and the GBM (subendothelial deposits), or between
the outer surface of the GBM and the podocytes (subepithelial
deposits).
Slide 84
molecular charge and size of these reactants are clearly
important
Slide 85
Highly cationic immunogens tend to cross the GBM, and the
resultant complexes eventually achieve a subepithelial
location.
Slide 86
Highly anionic macromolecules are excluded from the GBM and
either are trapped subendothelially or may, in fact, not be
nephritogenic at all.
Slide 87
Molecules with more neutral charge and immune complexes
containing these molecules tend to accumulate in the
mesangium.
Slide 88
Cell-Mediated Immunity in Glomerulonephritis sensitized T cells
cause some forms of glomerular injury and are involved in the
progression of many glomerulonephritides
Slide 89
Activation of Alternative Complement Pathway Alternative
complement pathway activation occurs in the clinicopathologic
entity called dense- deposit disease, also referred to as
membranoproliferative glomerulonephritis (MPGN type II). It may
also occur in some forms of proliferative glomerulonephritis. This
mechanism is discussed later, in the discussion of MPGN.
Slide 90
Epithelial Cell Injury changes in the visceral epithelial
cells, which include effacement of foot processes, vacuolization,
retraction, and detachment of cells from the GBM, and functionally
by proteinuria
Slide 91
Slide 92
GLOMERULAR DISEASES
Slide 93
1-Focal Segmental Glomerulosclerosis (FSGS). segmental and
eventually global sclerosis of glomeruli
Slide 94
Tubulointerstitial injury, manifested by tubular damage and
interstitial inflammation, is a component of many acute and chronic
glomerulonephritides. Tubulointerstitial fibrosis contributes to
progression in both immune and nonimmune glomerular diseases
Slide 95
ACUTE GLOMERULONEPHRITIS
Slide 96
This group of glomerular diseases is characterized anatomically
by inflammatory alterations in the glomeruli and clinically by the
syndrome of acute nephritis. The nephritic patient usually presents
with hematuria, red cell casts in the urine, azotemia
Slide 97
Acute Proliferative (Poststreptococcal, Postinfectious)
Glomerulonephritis characterized histologically by diffuse
proliferation of glomerular cells, associated with influx of
leukocytes. The inciting antigen may be exogenous or endogenou
s
Slide 98
Slide 99
The prototypic exogenous antigen- induced disease pattern is
postinfectious glomerulonephritis, The most common infections are
streptococcal, but the disorder has also been associated with other
infections. whereas that produced by an endogenous antigen is the
nephritis of systemic lupus erythematosus,
Slide 100
Poststreptococcal Glomerulonephritis It usually appears 1 to 4
weeks after a streptococcal infection of the pharynx or skin
(impetigo). Poststreptococcal glomerulonephritis occurs most
frequently in children 6 to 10 years of age, but adults of any age
can be affected.
Slide 101
Etiology and Pathogenesis. Only certain strains of group A -
hemolytic streptococci are nephritogenic, more than 90% of cases
being traced to types 12, 4, and 1, which can be identified by
typing of M protein of the cell wall.
Slide 102
Elevated titers of antibodies against one or more streptococcal
antigens are present in a great majority of patients. Serum
complement levels are low. The presence of granular immune deposits
in the glomeruli demonstrates an immune complex- mediated
mechanism, and so does the finding of electron-dense deposits.
Slide 103
There is also swelling of endothelial cells, and the
combination of proliferation, swelling, and leukocyte infiltration
obliterates the capillary lumens. There may be interstitial edema
and inflammation, and the tubules often contain red cell
casts.
Slide 104
By immunofluorescence microscopy, there are granular deposits
of IgG, IgM, and C3 in the mesangium and along the basement
membrane. The characteristic electron microscopic findings are
discrete, amorphous, electrondense deposits on the epithelial side
of the membrane, often having the appearance of "humps".
Slide 105
Slide 106
presumably representing the antigen- antibody complexes at the
epithelial cell surface. Subendothelial and intramembranous
deposits are also commonly seen, and mesangial deposits may be
present. There is often swelling of endothelial and mesangial
cells.
Slide 107
Clinical Course. In the classic case, a young child abruptly
develops malaise, fever, nausea, oliguria, and hematuria (smoky or
cocoa-colored urine) 1 to 2 weeks after recovery from a sore
throat. The patients exhibit red cell casts in the urine, mild
proteinuria (usually less than 1 mg/day), periorbital edema, and
mild to moderate hypertension.
Slide 108
In adults, the onset is more likely to be atypical, with the
sudden appearance of hypertension or edema, frequently with
elevation of BUN. Important laboratory findings include elevations
of antistreptococcal antibody (ASO) titers and a decline in the
serum concentration of C3 and other components of the complement
cascade and the presence of cryoglobulins in the serum.
Slide 109
less than 1% do not improve, become severely oliguric, and
develop a rapidly progressive form of glomerulonephritis. Prolonged
and persistent heavy proteinuria and abnormal GFR mark patients
with an unfavorable prognosis. In adults, the disease is less
benign.
Slide 110
Nonstreptococcal Acute Glomerulonephritis (Postinfectious
Glomerulonephritis) A similar form of glomerulonephritis occurs
sporadically in association with other bacterial infections (e.g.,
staphylococcal endocarditis, pneumococcal pneumonia, and
meningococcemia), viral disease (e.g., hepatitis B, hepatitis C,
mumps, human immunodeficiency virus [HIV] infection, varicella, and
infectious mononucleosis), and parasitic infections (malaria,
toxoplasmosis).
Slide 111
RAPIDLY PROGRESSIVE (CRESCENTIC) GLOMERULONEPHRITIS It is
characterized clinically by rapid and progressive loss of renal
function associated with severe oliguria and (if untreated) death
from renal failure within weeks to months.
Slide 112
Regardless of the cause, the classic histologic picture is
characterized by the presence of crescents in most of the glomeruli
(crescentic glomerulonephritis). these are produced in part by
proliferation of the parietal epithelial cells lining Bowman
capsule and in part by infiltration of monocytes and
macrophages.
Slide 113
Slide 114
Slide 115
Thus, a practical classification divides RPGN into three groups
on the basis of immunologic findings
Slide 116
TABLE 20-7 -- Rapidly Progressive Glomerulonephritis (RPGN)
Type I RPGN (Anti-GBM Antibody) Idiopathic Goodpasture syndrome
Type II RPGN (Immune Complex) Idiopathic Postinfectious Systemic
lupus erythematosus Henoch-Schnlein purpura (IgA) Others Type III
RPGN (Pauci-Immune) ANCA associated Idiopathic Wegener
granulomatosis Microscopic polyarteritis nodosa/microscopic
polyangiitis
Slide 117
The first type of RPGN is best remembered as anti-GBM antibody-
induced disease and hence is characterized by linear deposits of
IgG and, in many cases, C3 in the GBM. the anti-GBM antibodies
cross-react with pulmonary alveolar basement membranes to produce
the clinical picture of pulmonary hemorrhage associated with renal
failure (Goodpasture syndrome).
Slide 118
The Goodpasture antigen, as was noted earlier, is a peptide
within the noncollagenous portion of the 3 -chain of collagen type
IV.
Slide 119
Plasmapheresis to remove the pathogenic circulating antibodies
is usually part of the treatment, which also includes therapy to
suppress the underlying immune response.
Slide 120
The second type of RPGN is the result of immune
complex-mediated disease. It can be a complication of any of the
immune complex nephritides, including postinfectious
glomerulonephritis, SLE, IgA nephropathy, and Henoch-Schnlein
purpura. In all of these cases, immunofluorescence studies reveal
the granular pattern of staining characteristic of immune complex
deposition.
Slide 121
The third type of RPGN, also called pauci-immune type, is
defined by the lack of anti-GBM antibodies or immune complexes by
immunofluorescence and electron microscopy. Most patients with this
type of RPGN have antineutrophil cytoplasmic antibodies (ANCA), of
cytoplasmic (C) or perinuclear (P) patterns, in the serum, which,
as we have seen, play a role in some vasculitides.
Slide 122
Morphology The kidneys are enlarged and pale, often with
petechial hemorrhages on the cortical surfaces. Depending on the
underlying cause, the glomeruli may show focal necrosis, diffuse or
focal endothelial proliferation, and mesangial proliferation. The
histologic picture, however, is dominated by the formation of
distinctive crescents.
Slide 123
Electron microscopy may, as expected, disclose subepithelial
deposits in some cases, but in many cases, it shows distinct
ruptures in the GBM, the severe injury that allows leukocytes,
proteins, and inflammatory mediators into the urinary space, where
they trigger the crescent formation.
Slide 124
MEMBRANOUS GLOMERULOPATHY (MEMBRANOUS NEPHROPATHY) Membranous
glomerulopathy is the most common cause of the nephrotic syndrome
in adults. It is characterized by diffuse thickening of the
glomerular capillary wall and the accumulation of electron-dense,
immunoglobulin-containing deposits along the subepithelial side of
the basement membrane.
Slide 125
Slide 126
Slide 127
Slide 128
Slide 129
The most notable such associations are as follows : Drugs
Underlying malignant tumors SLE. Infections Other autoimmune
disorders
Slide 130
Exogenous (hepatitis B, Treponema antigens) or endogenous
(thyroglobulin) antigens have been identified within deposits in
some patients. the membrane attack complex. C5b-C9 causes
activation of glomerular epithelial and mesangial cells, inducing
them to liberate proteases and oxidants, which cause capillary wall
injury and increased protein leakage.
Slide 131
Morphology. By light microscopy, the glomeruli either appear
normal in the early stages of the disease or exhibit uniform,
diffuse thickening of the glomerular capillary wall. By electron
microscopy, the thickening is seen to be caused by irregular dense
deposits between the basement membrane and the overlying epithelial
cells.
Slide 132
These spikes are best seen by silver stains, which color the
basement membrane black. In time, these spikes thicken to produce
dome-like protrusions and eventually close over the immune
deposits. Immunofluorescence microscopy demonstrates that the
granular deposits contain both immunoglobulins and various amounts
of complement.
Slide 133
MINIMAL CHANGE DISEASE (LIPOID NEPHROSIS) This relatively
benign disorder is the most frequent cause of nephrotic syndrome in
children, but it is less common in adults. It is characterized by
diffuse effacement of foot processes of epithelial cells in
glomeruli that appear virtually normal by light microscopy.
Slide 134
Slide 135
The peak incidence is between 2 and 6 years of age. The disease
sometimes follows a respiratory infection or routine prophylactic
immunization. Its most characteristic feature is its usually
dramatic response to corticosteroid therapy.
Slide 136
Morphology. The glomeruli are normal by light microscopy.By
electron microscopy, the basement membrane appears normal, and no
electron-dense material is deposited. The principal lesion is in
the visceral epithelial cells, which show a uniform and diffuse
effacement of foot processes.
Slide 137
This change, often incorrectly termed "fusion" of foot
processes, actually represents simplification of the epithelial
cell architecture with flattening, retraction, and swelling of foot
processes. The visceral epithelial changes are completely
reversible after corticosteroid therapy.
Slide 138
The cells of the proximal tubules are often laden with lipid
and protein, reflecting tubular reabsorption of lipoproteins
passing through diseased glomeruli (thus, the historical term
lipoid nephrosis). Immunofluorescence studies show no
immunoglobulin or complement deposits
Slide 139
FOCAL SEGMENTAL GLOMERULOSCLEROSIS By light microscopy, the
segmental lesions may involve only a minority of the glomeruli and
may be missed if the biopsy specimen contains an insufficient
number of glomeruli. A morphologic variant of focal segmental
glomerulosclerosis, called collapsing glomerulopathy, is
characterized by collapse and sclerosis of the entire glomerular
tuft in addition to the usual focal segmental glomerulosclerosis
lesions.
Slide 140
MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS Membranoproliferative
glomerulonephritis (MPGN) is characterized histologically by
alterations in the basement membrane, proliferation of glomerular
cells, and leukocyte infiltration. Because the proliferation is
predominantly in the mesangium, a frequently used synonym is
mesangiocapillary glomerulonephritis.
Slide 141
Like many other glomerulonephritis, MPGN either can be
associated with other systemic disorders and known etiologic agents
(secondary MPGN) or may be idiopathic (primary MPGN). Primary MPGN
is divided into two major types on the basis of distinct
ultrastructural, immunofluorescent, and pathologic findings: type I
and type II MPGN (dense-deposit disease).
Slide 142
Morphology. By light microscopy, both types are similar. The
glomeruli are large and hypercellular. The hypercellularity is
produced both by proliferation of cells in the mesangium and
so-called endocapillary cell proliferation involving capillary
endothelium and infiltrating leukocytes. The glomeruli have a
"lobular" appearance.
Slide 143
Slide 144
The GBM is clearly thickened, often focally; this is most
evident in the peripheral capillary loops. The glomerular capillary
wall often shows a "double- contour" or "tram-track" appearance,
especially evident in silver or PAS stains. This is caused by
"duplication" of the basement membrane, usually as the result of
new basement membrane synthesis. Such interposition gives rise to
the appearance of "split" basement membranes.
Slide 145
Slide 146
Types I and II MPGN differ in their ultrastructural and
immunofluorescent features.
Slide 147
Type I MPGN (the great majority of cases) is characterized by
the presence of subendothelial electron-dense deposits. Mesangial
and occasional subepithelial deposits may also be present. By
immunofluorescence, C3 is deposited in a granular pattern, and IgG
and early complement components (C1q and C4) are often also
present, suggesting an immune complex pathogenesis.
Slide 148
Slide 149
In dense-deposit disease (type II MPGN) a relatively rare
entity, the lamina densa of the GBM is transformed into an
irregular, ribbon-like, extremely electron-dense structure because
of the deposition of dense material of unknown composition in the
GBM proper, giving rise to the term dense- deposit disease. C3 is
present in irregular granular or linear foci in the basement
membranes on either side but not within the dense deposits. C3 is
also present in the mesangium in characteristic circular aggregates
(mesangial rings). IgG is usually absent, as are the early-acting
complement components (C1q and C4).
Slide 150
Slide 151
In most cases of type I MPGN there is evidence of immune
complexes in the glomerulus and activation of both classical and
alternative complement pathways.
Slide 152
Most patients with dense-deposit disease (type II MPGN) have
abnormalities that suggest activation of the alternative complement
pathway. These patients have a consistently decreased serum C3 but
normal C1 and C4, the immune complex- activated early components of
complement. They also have diminished serum levels of factor B and
properdin, components of the alternative complement pathway. In the
glomeruli, C3 and properdin are deposited, but IgG is not.
Slide 153
More than 70% of patients with dense-deposit disease have a
circulating antibody termed C3 nephritic factor (C3NeF), which is
an autoantibody that binds to the alternative pathway C3
convertase
Slide 154
IgA NEPHROPATHY (BERGER DISEASE) This form of
glomerulonephritis is characterized by the presence of prominent
IgA deposits in the mesangial regions, detected by
immunofluorescence microscopy
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IgA nephropathy is a frequent cause of recurrent gross or
microscopic hematuria and is probably the most common type of
glomerulonephritis worldwide.Mild proteinuria is usually present,
and the nephrotic syndrome may occasionally develop. secondary IgA
nephropathy occurs in patients with liver and intestinal
diseases
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HEREDITARY SYNDROMES OF ISOLATED HEMATURIA Hereditary
heterogeneous nephritis refers to a group of familial renal
diseases associated primarily with glomerular injury. Two deserve
discussion: Alport syndrome, because the lesions and genetic
defects have been well studied, and thin basement membrane disease,
the most common cause of benign familial hematuria.
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Alport Syndrome Alport syndrome, when fully developed, is
manifest by nephritis progressing to chronic renal failure,
accompanied by nerve deafness and various eye disorders, including
lens dislocation, posterior cataracts, and corneal dystrophy. In
the most common X-linked form, males express the full syndrome, and
females are carriers in whom manifestations of disease are
typically limited to hematuria. Rare autosomal-recessive and
autosomal-dominant pedigrees also exist, in which males and females
are equally susceptible to the full syndrome.
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The characteristic findings of fully developed disease are seen
with the electron microscope and are found in most patients with
hereditary nephritis. The GBM shows irregular foci of thickening
alternating with attenuation (thinning), with pronounced splitting
and lamination of the lamina densa, often with a distinctive
basket-weave appearance. Similar alterations can be found in the
tubular basement.
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Immunohistochemistry can be helpful in cases with absent or
borderline basement membrane lesions, because antibodies to 3, 4,
and 5 collagen fail to stain both glomerular and tubular basement
membranes in the classic X-linked form. There is also absence of 5
staining in skin biopsy specimens.
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Pathogenesis. Defective GBM synthesis because of the production
of abnormal collagen type IV underlies the renal lesions. In
patients with X-linked disease, the defect is caused by mutations
in the gene encoding the 5 -chain of collagen type IV (COL4A5), a
component of the GBM.
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patients synthesize lesser amounts of other collagen
components, including the 3 - chain, which, as you recall, includes
the Goodpasture antigen, and the 4 -chain. Indeed, glomeruli from
patients with Alport syndrome who lack the 3 -chain fail to react
with anti-GBM antibodies from patients with Goodpasture syndrome.
In the autosomal-recessive pedigrees, mutations in the 3 - and 4
-chains have been reported
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Thin Basement Membrane Disease (Benign Familial Hematuria) This
is a fairly common entity manifested clinically by familial
asymptomatic hematuriausually uncovered on routine urinalysisand
morphologically by diffuse thinning of the GBM to between 150 and
250 nm (compared with 300 to 400 nm in normal adult individuals).
Although mild or moderate proteinuria may also be present, renal
function is normal and prognosis is excellent
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The disorder should be distinguished from IgA nephropathy,
another common cause of hematuria, and X-linked Alport
syndrome.
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CHRONIC GLOMERULONEPHRITIS
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Chronic glomerulonephritis is best considered a pool of
end-stage glomerular disease fed by a number of streams of specific
types of glomerulonephritis. The kidneys are symmetrically
contracted and have diffusely granular, cortical surfaces. On
section, the cortex is thinned, there eventually ensues hyaline
obliteration of glomeruli, transforming them into acellular
eosinophilic masses.
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Because hypertension is an accompaniment of chronic
glomerulonephritis, arterial and arteriolar sclerosis may be
conspicuous. Marked atrophy of associated tubules, irregular
interstitial fibrosis, and mononuclear leukocytic infiltration of
the interstitium also occur.
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Dialysis Changes: include arterial intimal thickening caused by
accumulation of smooth muscle-like cells and a loose,
proteoglycan-rich stroma; focal calcification, usually within
residual tubular segments; extensive deposition of calcium oxalate
crystals in tubules and interstitium; acquired cystic disease,
discussed earlier; and increased numbers of renal adenomas and
adenocarcinomas
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Uremic Complications: Patients dying with chronic
glomerulonephritis also exhibit pathologic changes outside the
kidney that are related to the uremic state and are also present in
other forms of chronic renal failure. Often clinically important,
these include uremic pericarditis, uremic gastroenteritis,
secondary hyperparathyroidism with nephrocalcinosis and renal
osteodystrophy, left ventricular hypertrophy due to hypertension,
and pulmonary changes of diffuse alveolar damage often ascribed to
uremia (uremic pneumonitis ).
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GLOMERULAR LESIONS ASSOCIATED WITH SYSTEMIC DISEASES
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Systemic Lupus Erythematosus The clinical manifestations can
include recurrent microscopic or gross hematuria, acute nephritis,
the nephrotic syndrome, chronic renal failure, and
hypertension.
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Henoch-Schnlein Purpura This syndrome consists of purpuric skin
lesions characteristically involving the extensor surfaces of arms
and legs as well as buttocks; abdominal manifestations including
pain, vomiting, and intestinal bleeding; nonmigratory arthralgia;
and renal abnormalities. IgA nephropathy and Henoch-Schnlein
purpura are spectra of the same disease.
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Bacterial Endocarditis Glomerular lesions occurring in the
course of bacterial endocarditis represent a type of immune complex
nephritis initiated by complexes of bacterial antigen and antibody.
Hematuria and proteinuria of various degrees characterize this
entity clinically.
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Diabetic Glomerulosclerosis Diabetes mellitus is a major cause
of renal morbidity and mortality, and diabetic nephropathy is one
of the leading causes of chronic kidney failure in the United
States. Advanced or end-stage kidney disease occurs in as many as
40% of both insulin-dependent type 1 diabetics and type 2
diabetics.
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Overt proteinuria is preceded by the development of lesser
degrees of protein leakage into the urine, termed
"microalbuminuria," which may occur within a few years of the onset
of diabetes. The increased GFR typical of early-onset type 1
diabetics is associated with microalbuminuria, which is defined as
urinary albumin excretion of 30 to 300 mg/day of albumin.
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Nodular Glomerulosclerosis. This is also known as
intercapillary glomerulosclerosis or Kimmelstiel- Wilson disease.
lesions are frequently accompanied by prominent accumulations of
hyaline material in capillary loops ("fibrin caps") or adherent to
Bowman's capsules ("capsular drops").
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Amyloidosis most commonly renal amyloid is of light-chain (AL)
or AA type. The typical Congo red amyloid-positive fibrillary
deposits are present within the mesangium and capillary walls and
rarely are localized to the subepithelial space.
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Fibrillary and Immunotactoid Glomerulonephritis The glomerular
lesions usually exhibit membranoproliferative or
mesangioproliferative patterns by light microscopy, and by
immunofluorescence microscopy, there is selective deposition of
IgG, often of IgG4 subclass, with complement C3 and Ig and light
chains also present. In immunotactoid glomerulopathy, a much rarer
condition, the deposits are microtubular in structure and 30 to 50
nm in width. Patients often have circulating paraproteins and/or
monoclonal immunoglobulin deposition in glomeruli.
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Essential mixed cryoglobulinemia is another systemic condition
in which deposits of cryoglobulins composed principally of IgG-IgM
complexes induce cutaneous vasculitis, synovitis, and a
proliferative glomerulonephritis, typically membranoproliferative
glomerulonephritis. Most cases of essential mixed cryoglobulinemia
have been associated with infection with hepatitis C virus.
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Plasma cell dyscrasias may also induce glomerular lesions.
Multiple myeloma and other dyscrasias producing circulating
monoclonal immunoglobulins are associated with (1) amyloidosis, in
which the fibrils are usually composed of monoclonal lambda light
chains, (2) deposition of monoclonal immunoglobulins or light
chains in glomerular basement membranes, and (3) distinctive
nodular glomerular lesions resulting from the deposition of
nonfibrillar light chains. This so- called light-chain or
monoclonal immunoglobulin deposition disease sometimes occurs in
the absence of overt myeloma and is usually characterized by
deposition of Ig light chains in glomeruli.
