1. Glomerular
Diseases
Lecture 38
Glomerulopathy

3. 3
Glomerulonephritis
• Nephros – kidney
• -itis – inflammation of
• Glomus – small round ball or knot
• Pathos – suffering or disease
• -osis – diseased condition
• Glomerulonephritis – inflammation of the glomeruli
• Glomerulopathy – disease of the glomeruli

4. Primary Glomerular Diseases
BKMC

6. Pathogenesis of Glomerular Disease
Immune
disorder
Kidney
involvement
Injury by
inflammation and
other mediators
Glomerular
dysfunction

7. Pathogenesis of Glomerular Disease
Immune
disorder
Glomerular
dysfunction
1. Circulating immune complex
2. Immune complex formation
3. Cell-mediated

8. Clinical Manifestations
BKMC
The clinical manifestations of glomerular disease are
clustered into the five major glomerular
syndromes summarized in Table .

9. HISTOLOGIC ALTERATIONS
Various types of glomerulopathies are
characterized by one or more of four basic
tissue reactions:
1.Hypercellularity
2.Basement membrane
thickening
3.Hyalinosis
4.Sclerosis

10. Minimal Change Disease (Lipoid Nephrosis)
• Benign disorder
• Most common in 1-7 years (Nephrotic synd)
• Pathogenesis: A T-cell derived factor
that causes podocyte damage and
effacement of foot processes.
1

11. Morphology
• Lipoid Nephrosis
• The uniform and diffuse effacement of the
foot processes of the podocytes.

12. Clinical features
• Nephrotic syndrome in an otherwise healthy
child
• Selective proteinuria ( chiefly albumin)
• >90% of cases respond to corticosteroid therapy

13. Focal & Segmental Glomerulosclerosis
• FSGS is characterised histologically by
sclerosis affecting
some glomeruli (focal involvement) &
involving only segments of each affected
glomerulus. FSGS is associated with the
nephrotic syndrome.
2

14. Pathogenesis(FSGS)
• Unknown
• Part of a continuum (MCD → FSGS)
• Distinct entities
• Injury to the podocytes is thought to
represent the initiating event of primary FSGS

15. Morphology (FSGS)
• The involvement is focal & segmental. The
affected glomeruli exhibit increased
mesangial matrix, obliterated capillary
lumens, and lipid droplets.
• EM shows effacement of foot processes.
Global sclerosis may be found occasionally.
• Collapsing glomerulopathy- Collapse of the
entire glomerular tuft & podocyte hyperplasia.

16. Clinical course
• Response to corticosteroid is poor and
• spontaneous remission of idiopathic FSGS is rare.
• 50% individuals suffer renal failure after 10 years.

17. 3.Membranous Glomerulonephritis
• Characterized morphologically by the
presence of subepithelial immunoglobulin-
containing deposits along the GBM.
• This is a slowly progressive disease,
• most common between 30 & 50 years of age.
• Well developed cases show diffuse thickening
of the capillary wall.

18. Membranous Glomerulonephritis (MG)
• Idiopathic = 85 %
• Secondary =15%
• Secondary to other disorders:
1. Infections
2. Malignant tumors
3. Autoimmune conditions
4. Exposure to inorganic salts
5.Drugs

19. Pathogenesisof MG
• Chronic Immune complex nephritis
• Most idiopathic forms are induced by
antibodies reacting in situ to endogenous
antigen.
• An autoimmune disease
• Activation of MAC→ Activation of mesangial
cell & podocytes→ liberate proteases &
oxidants→ damage capillary walls→
perturbations in filtration

20. Morphology
• LM: Diffuse thickening of the GBM
• EM: Subepithelial deposits (“Spike & dome”
pattern)
• Effacement of foot processes
• Immunofluorescence microscopy: Granular
deposits

21. Clinical Course
• Nephrotic syndrome
• Nonselective proteinuria
• Does not respond to corticosteroids
• Variable & Indolent course

22. 4
Membranoproliferative
Glomerulonephritis
Mesangiocapillary glomerulonephritis
MPGN is characterized histologically by
• alterations in the GBM
• proliferation of glomerular cells,
• leukocyte infiltration.

23. MPGN
• Because the proliferation is predominantly in
the mesangium but also may involve the
capillary loops, a frequently used synonym is
mesangiocapillary glomerulonephritis.
• MPGN accounts for 10% to 20% of cases of
nephrotic syndrome in children and young
adults.

24. Types of Primary MPGN

25. Pathogenesis (type I)
• 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.

26. Pathogenesis (type I)
• The antigens involved in idiopathic MPGN
are unknown.
• In many cases they are believed to be
proteins derived from
infectious agents such as hepatitis C
and B viruses.

27. Pathogenesis (type II)
• Most patients with dense-deposit disease
(type II MPGN) have abnormalities that
suggest activation of the
alternative complement
pathway.

28. Pathogenesis (type II)
• These patients have a consistently
decreased serum C3
but normal C1 and C4.

29. Pathogenesis (type II)
• 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.

30. Pathogenesis (type II)
• 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.
• Binding of the antibody stabilizes the
convertase, protecting it from enzymatic
degradation and thus favoring persistent C3
activation and hypocomplementemia.

31. Morphology of MPGN
By light microscopy both types of MPGN are
similar. The glomeruli are large and
hypercellular.

32. Morphology of MPGN
• Crescents are present in many cases.
The glomeruli have an accentuated
“lobular”
appearance due to the
proliferating mesangial cells and
increased mesangial matrix.

33. Morphology of MPGN
• The GBM is thickened.
• The glomerular capillary wall often shows a
“double-contour” or “tram-track”
appearance.

34. Morphologyof MPGN
Within the duplicated basement membranes
there is inclusion or interposition of cellular
elements, appearance of “split”
basement membranes.

35. • Types I and II MPGN differ in their ultrastructural
and immunofluorescent features.
• Type I MPGN is characterized by the presence of
discrete subendothelial electron-dense
deposits.
• 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.

36. Morphology of MPGN
• 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 due to
the deposition of dense material of unknown
composition in the GBM proper.

37. Morphology of MPGN
• 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).

39. A, Membranoproliferative glomerulonephritis, type I. Note discrete electron-dense deposits (arrows) incorporated into
the glomerular capillary wall between duplicated (split) basement membranes (double arrows), and in mesangial regions
(M); CL, capillary lumen. B, Dense-deposit disease (type II membranoproliferative glomerulonephritis). There are
markedly dense homogeneous deposits within the basement membrane proper. CL, capillary lumen. In both, mesangial
interposition gives the appearance of split basement membranes when viewed in the light microscope. C, Schematic
representation of patterns in the two types of membranoproliferative GN. In type I there are subendothelial deposits;
type II is characterized by intramembranous dense deposits (dense-deposit disease). In both, mesangial interposition
gives the appearance of split basement membranes when viewed in the light microscope.

40. Clinical Features.
Most patients present in adolescence or as young
adults with nephrotic syndrome and a nephritic
component manifested by hematuria or, more
insidiously, as mild proteinuria.
Few remissions occur spontaneously in either type,
and the disease follows a slowly progressive but
unremitting course.
Some patients develop numerous crescents and a
clinical picture of RPGN.
About 50% develop chronic renal failure within 10
years.

41. Clinical features
Treatments with steroids, immunosuppressive
agents, and antiplatelet drugs have not been
proved to be materially effective. There is a
high incidence of recurrence in transplant
recipients, particularly in dense-deposit
disease; dense deposits may recur in 90% of
such patients, although renal failure in the
allograft is much less common.

42. Secondary MPGN
Secondary MPGN (invariably type I) is more common
in adults and arises in the following settings:
• Chronic immune complex disorders, such as SLE;
hepatitis B infection; hepatitis C infection, usually
with cryoglobulinemia; endocarditis; infected
ventriculoatrial shunts; chronic visceral abscesses;
HIV infection; and schistosomiasis.

43. SecondaryMPGN
• α1-Antitrypsin deficiency
• Malignant diseases (chronic lymphocytic
leukemia and lymphoma)
• Hereditary deficiencies of complement
regulatory proteins

44. IgA nephropathy
• AKA IgA nephritis, IgAN, Berger's
disease, Berger's syndrome and
synpharyngitic glomerulonephritis) is a
form of
glomerulonephritis.

45. 5. IgA Nephropathy (Berger Disease)
• Characterized by the presence of prominent
IgA deposits in the
mesangial regions, detected by
immunofluorescence microscopy.

46. IgA Nephropathy (Berger Disease)

47. Pathogenesis
• In IgA nephropathy, plasma polymeric IgA is
increased, and circulating IgA-containing
immune complexes are present in some
patients. Only IgA1 forms the nephritogenic
deposits of IgA nephropathy.

48. IgA Nephropathy (Berger Disease)
Pathogenesis
• The prominent mesangial deposition of IgA
suggests entrapment of IgA immune
complexes in the mesangium, and the
presence of C3 combined with the absence of
C1q and C4 in glomeruli points to activation
of the alternative complement pathway and
initiate glomerular injury. .

49. IgA Nephropathy (Berger Disease)
• A genetic influence is suggested by the
occurrence of this condition in families and
in HLA-identical brothers and the increased
frequency of certain HLA and complement
genotypes in some populations.

50. Morphology
On histologic examination the lesions vary
considerably.
• The glomeruli may be normal or may show
• mesangial widening and endocapillary
proliferation (mesangioproliferative
glomerulonephritis),
• segmental proliferation confined to some
glomeruli (focal proliferative glomerulonephritis),
• or rarely, overt crescentic glomerulonephritis.

51. Morphology
• The characteristic immunofluorescent picture
is of mesangial deposition of IgA, often with
C3 and properdin and lesser amounts of IgG
or IgM. Early complement components are
usually absent.

53. Clinical Features
The disease affects people of any age, but older
children and young adults are most commonly
affected.
Many patients present with gross hematuria after an
infection of the respiratory or, less commonly,
gastrointestinal or urinary tract.

54. Clinical Features
• 30% to 40% have only microscopic
hematuria, with or without proteinuria; and
5% to 10% develop a typical acute nephritic
syndrome.

55. Clinical Features
• The hematuria typically lasts for several days
and then subsides, only to return every few
months. The subsequent course is highly
variable.

56. Clinical Features
• Many patients maintain normal renal
function for decades. Slow progression to
chronic renal failure occurs in 15% to 40%
of cases over a period of 20 years.

57. Clinical Features
• Onset in old age, heavy proteinuria,
hypertension, and the extent of
glomerulosclerosis on biopsy are clues to an
increased risk of progression.
• Recurrence of IgA deposits in transplanted
kidneys is frequent.

58. Clinical Features
• In approximately 15% of those with recurrent
IgA deposits, there is resulting clinical
disease, which most frequently runs the
same slowly progressive course as that of the
primary IgA nephropathy.

59. 6. Acute Proliferative (Poststreptococcal,
Postinfectious) Glomerulonephritis
Characterized histologically by
• diffuse proliferation of glomerular cells,
associated with influx of leukocytes.
• These lesions are typically caused by immune
complexes.
• The inciting antigen may be exogenous
(Postinfectious glomerulonephritis) or
endogenous (SLE).

60. Acute Proliferative Glomerulonephritis
• The most common underlying infections are
streptococcal, but the
disorder also has been associated with other
infections.

61. Poststreptococcal Glomerulonephritis
• It usually appears 1 to 4 weeks after a
streptococcal infection of the pharynx or
skin.
• It occurs most frequently in children 6 to 10
years of age, but adults of any age can also
be affected.

62. Etiology and Pathogenesis.
Only certain strains of group A β-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.

63. Etiology & Pathogenesis of Ac Prolif. G
• Poststreptococcal glomerulonephritis is an
immunologically mediated disease.
• Elevated titers of antibodies against one or
more streptococcal antigens are present in a
great majority of patients.

64. Etiology & Pathogenesis of Ac Prolif. G
• Serum complement levels are low,
• There are granular immune deposits in the
glomeruli, supporting an immune complex–
mediated mechanism.

65. Etiology & Pathogenesis
• Several cationic antigens, including a
nephritis-associated streptococcal plasmin
receptor (NAPlr), unique to
nephritogenic strains of streptococci, can be
found in affected glomeruli.

66. Etiology & PathogEnEsis
• Streptococcal pyogenic exotoxin B (SpeB)
and its zymogen precursor (zSpeB), are the
principal antigenic determinants in most
cases of poststreptococcal
glomerulonephritis.

67. Morphology.
• The classic diagnostic picture is
enlarged,
hypercellular
glomeruli.

68. Morphology of APG
• 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.

69. Morphology of APG
• By immunofluorescence microscopy, there
are granular deposits of IgG, IgM, and C3
in the mesangium and along the GBM.

70. Morphology of APG
• The characteristic electron microscopic
findings are discrete, amorphous,
electron-dense deposits
on the epithelial side of the membrane, often
having the appearance of “humps”.

72. Clinical Features Of APG
In the classic case, a young child abruptly
develops
malaise, fever, nausea, oliguria, and hematuria
1 to 2 weeks after recovery from a sore
throat.

73. Clinical features of Acute Proliferative Glomerulonephritis
The patients have red cell casts in the urine,
mild proteinuria (usually less than 1 gm/day),
periorbital edema, and mild to moderate
hypertension.

74. Clinical features of Acute Proliferative
Glomerulonephritis
In adults the onset is more likely to
be atypical, such as the sudden appearance
of hypertension or edema, frequently with
elevation of BUN.

75. Clinical features of Acute
Proliferative Glomerulonephritis
• During epidemics caused by nephritogenic
streptococcal infections, glomerulonephritis
may be asymptomatic, discovered
only on screening for microscopic hematuria.

76. Laboratory Findings
• Elevations of antistreptococcal antibody
titers and a decline in the serum
concentration of C3 and other components of
the complement cascade.

77. Prognosis
• More than 95% of affected children
eventually recover totally with conservative
therapy aimed at maintaining sodium and
water balance.
• A small minority of children (perhaps fewer
than 1%) do not improve, become severely
oliguric, and develop a rapidly progressive
form of glomerulonephritis.

78. Nonstreptococcal Acute
Glomerulonephritis (Postinfectious
Glomerulonephritis)
Glomerulonephritis occurs sporadically in
association with other infections, including
bacterial viral and parasitic.
Granular immunofluorescent deposits and
subepithelial humps are present.

79. 7. RAPIDLY PROGRESSIVE (CRESCENTIC)
GLOMERULONEPHRITIS
RPGN is a syndrome associated
with severe glomerular injury and
does not denote a specific
etiologic form of
glomerulonephritis.

80. RPGN
It is characterized clinically by
rapid and progressive loss of renal function
associated with severe oliguria and signs of
nephritic syndrome;
if untreated, death from renal failure occurs
within weeks to months.

81. RAPIDLY PROGRESSIVE (CRESCENTIC)
GLOMERULONEPHRITIS
• The most common histologic picture is the
presence of crescents in most of the
glomeruli (crescentic glomerulonephritis).

82. Crescents are produced by the proliferation
of the parietal epithelial cells lining Bowman
capsule and by the infiltration of monocytes
and macrophages.

83. Classification and Pathogenesis
RPGN may be caused by a number of different
diseases, some restricted to the kidney and
others systemic. Although no single mechanism
can explain all cases, there is little doubt that in
most cases the glomerular injury is
immunologically mediated.

84. Classification and Pathogenesis
• A practical classification divides RPGN into
three groups on the basis of
immunological findings.
• In each group the disease may be associated
with a known disorder, or it may be
idiopathic.

86. RAPIDLY PROGRESSIVE (CRESCENTIC)
GLOMERULONEPHRITIS
The first type of RPGN is anti-GBM
antibody–induced disease, characterized
by linear deposits of IgG and, in many cases,
C3 in the GBM that are visualized by
immunofluorescence.

87. Classification and Pathogenesis
• In some of these patients, 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).

88. RAPIDLY PROGRESSIVE (CRESCENTIC)
GLOMERULONEPHRITIS
The second type of RPGN is the result of
immune complex deposition. It can be a
complication of any of the immune complex
nephritides, including postinfectious
glomerulonephritis, lupus nephritis, IgA
nephropathy, and HenochSchönlein purpura.

89. Classification & Pathogenesis
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.

90. • To summarize, all three types of RPGN may
be associated with a well-defined renal or
extrarenal disease, but in many cases
( 50%), the disorder is idiopathic.∼

91. Of the patients with this syndrome, about one
fifth have anti–GBM antibody–mediated
glomerulonephritis without lung
involvement;
another one fourth have immune complex–
mediated crescentic glomerulonephritis;
and the remainder are of the pauci-immune
type.
The common denominator in all types of RPGN
is severe glomerular injury.

92. Morphology RPG
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.

93. Morphology
Crescents are
formed by proliferation of parietal cells and
by migration of monocytes and macrophages
into the urinary space.

94. Morphology
Fibrin strands are frequently
prominent between the cellular layers in the
crescents.

95. Morphology
By immunofluorescence microscopy, immune
complex–mediated cases show granular
immune deposits; Goodpasture syndrome
cases show linear GBM fluorescence for Ig
and complement, and pauci-immune cases
have little or no deposition of immune
reactants.

96. Morphology
Electron microscopy discloses deposits in those
cases due to immune complex deposition (type
II).
Regardless of type, electron microscopy may
show distinct ruptures in the GBM, the severe
injury that allows leukocytes, proteins, and
inflammatory mediators to reach the urinary
space, where they trigger the crescent
formation.

99. Clinical Course
Hematuria
Red blood cell casts in the urine,
Moderate proteinuria
Hypertension
Edema.

100. Clinical Course
In Goodpasture syndrome the course may be
dominated by recurrent hemoptysis
or even life-threatening
pulmonary
hemorrhage.

101. 8. CHRONIC GLOMERULONEPHRITIS
A pool of end-stage glomerular disease caused
specific types of glomerulonephritis:
Poststreptococcal glomerulonephritis in adults.
• Crescentic glomerulonephritis,
• Membranous nephropathy,
• MPGN,
• IgA nephropathy,
• FSGS

103. Chronic Glomerulonephritis
A variable percentage of cases arise
mysteriously with no antecedent
history of any of the well-recognized
forms of acute glomerulonephritis.

104. Morphology
• The kidneys are symmetrically contracted
and have diffusely granular cortical surfaces.
On section, the cortex is thinned, and there is
an increase in peripelvic fat.

105. Chronic Glomerulonephritis
In early cases, the glomeruli may still show
evidence of the primary disease. However,
there eventually ensues obliteration of
glomeruli, transforming them into acellular
eosinophilic masses.

106. Chronic Glomerulonephritis
• Arterial and arteriolar sclerosis
• Marked atrophy of associated tubules,
• Iirregular interstitial fibrosis,
• Mononuclear leukocytic infiltration of the
interstitium

107. Dialysis Changes
• Arterial intimal thickening
• Focal calcification,
• Extensive deposition of calcium oxalate
crystals in tubules and interstitium;
• Acquired cystic disease
• Increased numbers of renal adenomas and
adenocarcinomas.

108. Uremic Complications
Uremic pericarditis,
Uremic gastroenteritis,
Secondary hyperparathyroidism
Left ventricular hypertrophy
Uremic pneumonitis

110. Clinical Course
• Mostly CG develops insidiously and slowly
progresses to renal insufficiency or death from
uremia.
• Frequently, patients have loss of appetite,
anemia, vomiting, or weakness.

111. Clinical course of CG
In some, the renal disease is suspected with
the discovery of proteinuria, hypertension, or
azotemia on routine medical examination.
In others, the underlying renal disorder is
discovered in the course of investigation of
edema.

112. Clinical course of CG
Most patients are hypertensive, and sometimes
the dominant clinical manifestations are
cerebral or cardiovascular.