GLOMERULAR DISEASES

• The glomerulus consists of an anastomosing

network of capillaries invested by two layers of
epithelium.
• The visceral epithelium (composed of
podocytes) is an intrinsic part of the capillary
wall, whereas
• the parietal epithelium lines Bowman
space(urinary space), the cavity in which
plasma ultrafiltrate first collects.
• The glomerular capillary wall is the filtration unit and
consists of the following structures
I. A thin layer of fenestrated endothelial cells, each
fenestration being 70 to 100 nm in diameter
II. 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. The GBM consists of
collagen (mostly type IV), laminin, polyanionic
proteoglycans, fibronectin, and several other
glycoproteins.
I. Podocytes, which are structurally complex cells that
possess interdigitating processes embedded in and
adherent to the lamina rara externa of the basement
membrane. Adjacent foot processes are separated by
20- to 30-nm-wide filtration slits,
II. The glomerular tuft is supported by mesangial cells lying
between the capillaries. These cells, of mesenchymal
origin, are contractile and are capable of proliferation, of
laying down collagen and other matrix components, and
of secreting a number of biologically active mediators.
 Mechanisms of Glomerular Injury and
Disease
• Antibody-mediated immune injury is an important mechanism of
glomerular damage, mainly by way of complement and leukocyte-
mediated pathways.
• Antibodies also may be directly cytotoxic to cells in the
glomerulus.
• The most common forms of antibody-mediated GN are caused by
the formation of immune complexes, whether occurring in situ or
by deposition of circulating immune complexes.
• These immune complexes may contain exogenous(e.g. microbial)
circulating antigens or endogenous antigens (e.g. in membranous
nephropathy).
• Immune complexes show a granular pattern of deposition
• Autoantibodies against components of the
GBM are the cause of anti-GBM-antibody–
mediated disease, often associated with
severe injury.
• The pattern of antibody deposition is linear
• Glomerular disease may present clinically as
nephrotic or nephritic syndrome. Their clinical
features are different.
• Renal biopsy can yield a definitive diagnosis
when light microscopy features are considered
in concert with immunofluorescence (IF) and
electron microscopy (EM)
 Nephrotic Syndrome
• The nephrotic syndrome refers to a clinical complex that
includes
• Massive proteinuria, with daily protein loss in the urine
of 3.5 g or more in adults
• Hypoalbuminemia, with plasma albumin levels less
than
3 g/dL
• Generalized edema, the most obvious clinical
manifestation
• Hyperlipidemia and lipiduria
 Minimal-Change Disease

• Minimal-change disease, a relatively benign

disorder, is the most frequent cause of the
nephrotic syndrome in children.
• Characteristically, the glomeruli have a normal
appearance by light microscopy but show diffuse
effacement of podocyte foot processes when viewed
with the electron microscope.
• Although it may develop at any age, this condition is
most common between the ages of 1 and 7 years.
Clinical Course
• The disease manifests with the insidious
development of the nephrotic syndrome in an
otherwise healthy child.
• There is no hypertension, and renal function is
preserved in most of these patients.
• The protein loss usually is confined to the
smaller plasma proteins, chiefly
albumin(selective proteinuria).
• The prognosis for children with this disorder is
good. More than 90% of children respond to a
short course of corticosteroid therapy;
• however, proteinuria recurs in more than two
thirds of the initial responders, some of whom
become steroid-dependent.
• Less than 5% develop chronic kidney disease
 Focal Segmental
Glomerulosclerosis
• Focal segmental glomerulosclerosis (FSGS) is
characterized histologically by sclerosis affecting some but
not all glomeruli (focal involvement) and involving only
segments of each affected glomerulus (segmental
involvement).
• This histologic picture often is associated with nephrotic
syndrome.
• FSGS may be primary (idiopathic) or secondary to one of
the following conditions: HIV infection (HIV nephropathy),
heroin abuse (heroin nephropathy), IgA nephropathy …
• Primary FSGS accounts for approximately 20% to 30%
of all cases of the nephrotic syndrome.
• It is an increasingly common cause of nephrotic
syndrome in adults and remains a frequent cause in
children.
Clinical Course
• In children it is important to distinguish FSGS as a
cause of the nephrotic syndrome from minimal-change
disease, because the clinical courses are markedly
different.
• The incidence of hematuria and hypertension
is higher in persons with FSGS than in those
with minimal-change disease; the FSGS
associated proteinuria is nonselective; and in
general the response to corticosteroid therapy
is poor.
• At least 50% of patients with FSGS develop
end-stage kidney disease within 10 years of
diagnosis.
 Membranous Nephropathy

• Membranous nephropathy is a slowly

progressive disease, most common between
30 and 60 years of age.
• It is characterized morphologically by the
presence of subepithelial immunoglobulin-
containing deposits along the GBM.
• Early in the disease, the glomeruli may appear
normal by light microscopy, but well-
developed cases show diffuse thickening of
the capillary wall.
• In the remainder (secondary membranous nephropathy), it occurs
secondary to other
disorders, including
• Infections (chronic hepatitis B, syphilis, schistosomiasis,malaria)
• Malignant tumors, particularly carcinoma of the lung and colon
and melanoma
• Systemic lupus erythematosus and other autoimmune
conditions
• Exposure to inorganic salts (gold, mercury)
• Drugs (penicillamine, captopril, nonsteroidal antiinflammatory
agents)
Clinical Course
• Most cases of membranous nephropathy present as
full blown nephrotic syndrome
• although proteinuria persists in greater than 60% of
patients with membranous nephropathy, only about
40% suffer progressive disease terminating in renal
failure after 2 to 20 years.
• An additional 10% to 30% have a more benign course
with partial or complete remission of proteinuria.
 Nephritic Syndrome
• The nephritic syndrome is a clinical complex, usually of
acute onset, characterized by
(1) hematuria with dysmorphic red cells and red cell casts
in the urine;
(2) some degree of oliguria and azotemia; and
(3) hypertension.
(4) edema
• Although proteinuria and even edema also may be
present, these usually are not as severe as in the
nephrotic syndrome.
• The lesions that cause the nephritic syndrome
have in common proliferation of the cells
within the glomeruli, often accompanied by an
inflammatory leukocytic infiltrate.
• This inflammatory reaction severely injures
the capillary walls, permitting blood to pass
into the urine and inducing hemodynamic
changes that lead to a reduction in the GFR.
• The acute nephritic syndrome may be
produced by systemic disorders such as
systemic lupus erythematosus, or
• it may be secondary to primary glomerular
diseases such as acute postinfectious GN.
 Acute Postinfectious
Glomerulonephritis
• Acute postinfectious GN, one of the more frequently
occurring glomerular disorders, is caused by glomerular
deposition of immune complexes resulting in proliferation
of and damage to glomerular cells and infiltration of
leukocytes, especially neutrophils.
• The inciting antigen may be exogenous or endogenous.
• Acute Postinfectious Glomerulonephritis incited by
exogenous antigens could be caused by - poststreptococcal
GN(prototypical), pneumococcal and staphylococcal
Infections, viral diseases such as mumps, measles,
chickenpox, and hepatitis B and C.
• Endogenous antigens, as occur in systemic
lupus erythematosus, also may cause a
proliferative GN but more commonly result in
a membranous nephropathy
 Poststreptococcal GN
• Classic case of poststreptococcal GN develops
in a child 1 to 4 weeks after they recover from
a group A streptococcal infection.
• Only certain “nephritogenic” strains of β-
hemolytic streptococci evoke glomerular
disease.
• In most cases, the initial infection is localized
to the pharynx or skin.
Clinical Course
• The onset of the kidney disease tends to be abrupt, heralded
by malaise, a slight fever, nausea, and the nephritic syndrome.
• In the usual case, oliguria, azotemia, and hypertension are only
mild to moderate.
• Characteristically, there is gross hematuria, smoky brown
urine. Some degree of proteinuria is a constant feature of the
disease, it occasionally may be severe enough to produce the
nephrotic syndrome.(nephritic nephrotic syndrome)
• Serum anti–streptolysin O (ASO)antibody titers are elevated in
poststreptococcal cases
Complications
Recovery occurs in most children
• Some children develop rapidly progressive GN
• chronic renal disease from secondary scarring
• Both could end up with ESRD in 15% to 50% of
the cases in adults in 1 to 2 decades
 IgA Nephropathy
• This condition usually affects children and
young adults and
• Begins as an episode of gross hematuria that
occurs within 1 or 2 days of a nonspecific
upper respiratory tract infection.
• Hematuria lasts several days and then
subsides, only to recur every few months
• The hallmark of the disease is the deposition
of IgA in the mesangium.
• Slow progression to chronic renal failure
 Rapidly Progressive
Glomerulonephritis
• Rapidly progressive glomerulonephritis (RPGN) is a
clinical syndrome and not a specific etiologic form of
GN.
• It is characterized by progressive loss of renal function
• Laboratory findings typical of the nephritic syndrome,
and often severe oliguria.
• If untreated, it leads to death from renal failure within a
period of weeks to months.
• The characteristic histologic finding associated with
RPGN is the presence of crescents (crescentic GN).
• The diseases causing crescentic GN may be
associated with a known disorder or it may be
idiopathic.
• When the cause can be identified, about 12%
of the patients have anti-GBM antibody–
mediated crescentic GN with (Goodpasture
syndrome) or without lung involvement; 44%
have immune complex GN with crescents; and
the remaining 44% have pauciimmune
crescentic GN.
Clinical Course
• The onset of RPGN is much like that of the
nephritic syndrome, except that the oliguria
and azotemia are more pronounced.
• Proteinuria sometimes approaching nephrotic
range may occur.
• Some affected persons become anuric and
require long-term dialysis or transplantation.
• The prognosis can be roughly related to the
fraction of involved glomeruli:
– Patients in whom crescents are present in less
than 80% of the glomeruli have a better prognosis
than those in whom the percentages of crescents
are higher
 CHRONIC KIDNEY DISEASE
• Chronic kidney disease is the result of progressive
scarring resulting from any type of kidney disease.
• Alterations in the function of remaining initially intact
nephrons are ultimately maladaptive and cause further
scarring.
• This eventually results in an end-stage kidney where
glomeruli, tubules, interstitium and vessels are
sclerosed, regardless of the primary site of injury.
• Unless the disorder is treated with dialysis or
transplantation, death from uremia results.
Morphological changes related to CKD include
• symmetrically contracted kidneys
• Scaring and obliteration of the glomeruli
• interstitial fibrosis
• As damage to all structures progresses, it may
become difficult to ascertain whether the primary
lesion was glomerular, vascular, tubular, or
interstitial. Such markedly damaged kidneys have
been designated end stage kidneys
Clinical Course
• Chronic kidney disease is the end stage of many different
renal diseases.
• Clinically, it causes
– progressive irreversible azotemia
– normocytic anemia
– platelet dysfunction
– renal osteodystrophy and
– hypertension.
• It is characterized pathologically by bilaterally shrunken
kidneys.
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