Debre Markos University

School of Medicine
Renal Pathology for PC2
By: Zelalem Tadesse(MD)
July, 2018

1
 Introduction
• 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.

2
 Clinical Manifestations of Renal
Diseases
• Before we list the syndromes, a few terms must be
defiend.
 Azotemia: ↑ BUN and creatinine, due to ↓ GFR;
causes are prerenal (shock), renal and postrenal
(obstruction)
 Uremia: azotemia plus clinical signs/symptoms
associated with chronic renal failure

3
 Cont’d…
1. Acute nephritic syndrome
Hematuria, hypertension, azotemia, oliguria, mild
edema, RBCs casts, proteinuria 20 to postinfectious,
diffuse crescentic & membranoproliferative GN
RPGN is characterized as a nephritic syndrome with
rapid decline (hours to days) in GFR.

4
 Cont’d….
2 Nephrotic syndrome
-Proteinuria > 3.5 g/day, hypoalbuminemia (<3 g/dl),
hyperlipidemia, lipiduria, severe edema (anasarca)
-Prone to infections due to loss of immunoglobulins
and factor B of complement thrombosis and
thromboemboli are due to loss of anticoagulants
such as antithrombin III and antiplasmin

5
 Cont’d….
3. Acute renal failure is dominated by oliguria or
anuria (reduced or no urine flow), and recent onset
of azotemia.
It can result from glomerular, interstitial, or vascular
injury or acute tubular injury.
4. Chronic renal failure, characterized by prolonged
symptoms and signs of uremia, is the end result of all
chronic renal parenchymal diseases.

6
 Cont’d….
5. 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
involvement of the lower ( cystitis, prostatitis,
urethritis).

7
Cont’d….

8
Glomerular Diseases

9
 Introduction
• Glomerulus consists of an anastomosing network of
capillaries invested by two layers of epithelium.
 Visceral epithelium (podocytes) is an intrinsic part of
the capillary wall.
 Parietal epithelium lines Bowman space (urinary
space), the cavity in which plasma ultrafiltrate first
collects.

10
 Glomerular Capillary Wall

Components
Fenestrated endothelial cells- 70 to 100 nm in
diameter.
Glomerular basement membrane (GBM)
Visceral epithelial cells (podocytes)
The entire glomerular tuft is supported by mesangial
cells lying between the capillaries.

11
 Characteristics of Glomerular Filtration

• High permeability to water and small solutes.

• Impermeability to molecules of the size and
molecular charge of albumin (Size: 3.6 nm radius;
70,000 kD).
– The larger, the less permeable.
• The more cationic, the more permeable.
– B/c many anionic molecules present within the
wall, including the acidic proteoglycans of the
GBM and the sialoglycoproteins of epithelial and
endothelial cell coats.

12
 Primary Glomerulopathies
-Acute proliferative glomerulonephritis
Post-infectious
-Rapidly progressive (crescentic) glomerulonephritis
-Membranous glomerulopathy
-Minimal-change disease
- Focal segmental glomerulosclerosis
-Membranoproliferative glomerulonephritis
-IgA nephropathy
-Chronic glomerulonephritis

13
 Systemic Diseases with Glomerular
Involvement
• Systemic lupus erythematosus
• Diabetes mellitus
• Amyloidosis
• Goodpasture syndrome
• Microscopic polyarteritis/polyangiitis
• Wegener granulomatosis
• Henoch-Schönlein purpura
• Bacterial endocarditis
14
 Hereditary Disorders

• Alport syndrome
• Thin basement membrane disease
• Fabry disease

15
 Pathogenesis of Glomerular injury
• Although much is not known about etiologic agents and
triggering events, it is clear that immune mechanisms
underlie most forms of primary glomerulopathy and
many of the secondary glomerular disorders.
• Two forms of antibody-associated injury have been
established:
– 1. Deposition of soluble circulating antigen-antibody
complexes in the glomerulus, and
– 2. Injury by antibodies reacting in situ within the glomerulus,
either with insoluble fixed (intrinsic) glomerular antigens or
with molecules planted within the glomerulus

16
Nephritis Caused by Circulating Immune
Complexes
• Type III hypersensitivity reactions.
• Glomerulus considered as an "innocent bystander"
because it does not incite the reaction.
• The antigen is not of glomerular origin.
• Antigen-antibody complexes are formed in situ or in
the circulation and are then trapped in the
glomeruli.
• Injury by activation of complement and the
recruitment of leukocytes.
17
 Cont’d....
• Glomerular lesions usually consist of
leukocytic infiltration (exudation) into
glomeruli and variable proliferation of
endothelial, mesangial, and parietal epithelial
cells.
• EM-reveals the immune complexes as
electron-dense deposits.
• The pattern of immune complex deposition is
helpful in distinguishing various types of GN.

18
Nephritis Caused by In Situ Immune Complexes

• Antibodies in this form of injury react directly with

fixed or planted antigens in the glomerulus.
• Anti-Glomerular Basement Membrane (GBM)
Antibody Glomerulonephritis
– Antibodies are directed against fixed antigens in the
GBM.
• Antibody binds to the antigen α3 chain epitope in the
collagenase-resistant component of collagen IV located in the
lamina densa.
– Formation of autoantibodies directed against the GBM.
– A linear pattern of staining when the bound antibodies
are visualized with immunofluorescence microscopy.
– Less than 1% of human GN cases.
19
 Cont’d....
• Antibodies may also react in situ with previously
"planted" non-glomerular antigens, which may localize
in the kidney by interacting with various intrinsic
components of the glomerulus.
• Glomerular localization of antigen, antibody, or
complexes:
– Complexes deposited in the proximal zones of the GBM
(endothelium or subendothelium) elicit an inflammatory
reaction in the glomerulus with infiltration of leukocytes.
– Antibodies directed to distal zones of the GBM (epithelium
and subepithelium) are largely noninflammatory and elicit
lesions similar to those of Heymann nephritis or
membranous nephropathy.

20
Immunological mechanisms of glomerulonephritis.
21
 Cell-Mediated Immune
Glomerulonephritis
• Sensitized T cells, formed during the course of a
cell-mediated immune reaction, can cause
glomerular injury.
• T cell-mediated injury may account for the
instances of GN in which either there are no
deposits of antibodies or immune complexes or
the deposits do not correlate with the severity of
damage.
• Even when antibodies are present, T-cell-
mediated injury cannot be excluded.
22
 Mediators of Immune Injury
• Glomerular damage, reflected by loss of glomerular
barrier function, is manifested by proteinuria and, in
some instances, by reductions in GFR.
• How does glomerular damage ensue?
– Major pathway of antibody-initiated injury is complement-
leukocyte-mediated
– Activation of complement leads to the generation of
chemotactic agents (mainly C5a) and the recruitment of
neutrophils and monocytes.
– Neutrophils release proteases, which cause GBM degradation;
oxygen-derived free radicals, which cause cell damage; and
arachidonic acid metabolites, which contribute to reduction in
GFR.

23
 Cont’d...
• Antibodies directed to glomerular cell antigens may also
be directly cytotoxic to glomerular cells.
• Other mediators of glomerular damage include :
– (1) Monocytes and macrophages
• Infiltrate the glomerulus in antibody- and cell-mediated reactions and,
when activated, release a vast number of biologically active molecules.
– (2) Platelets
• Aggregate in the glomerulus during immune-mediated injury and
release prostaglandins and growth factors.
– (3) Glomerular cells
• (epithelial, mesangial, and endothelial), which can be stimulated to
secrete mediators such as cytokines (interleukin 1), arachidonic acid
metabolites, growth factors, nitric oxide, and endothelin; and
– (4) Fibrin-related products
• Which cause leukocyte infiltration and glomerular cell proliferation as
a consequence of intraglomerular thrombosis.
24
Other Mechanisms of Glomerular Injury
• Podocyte Injury
– Induced by antibodies to visceral epithelial cell
antigens; by toxins, as in an experimental model of
proteinuria induced by puromycin aminonucleoside.
– Morphologic changes in the podocytes, which
include effacement of foot processes, vacuolization,
and retraction and detachment of cells from the
GBM, and functionally by proteinuria.
– Loss of normal slit diaphragms is key in the
development of proteinuria.
25
 Cont’d...
• Nephron Loss
– Once any renal disease, glomerular or otherwise,
destroys sufficient functioning nephrons to reduce the
GFR to 30% to 50% of normal, progression to end-stage
renal failure often proceeds inexorably, although the rate
varies.
– Such individuals develop proteinuria, and their kidneys
show widespread glomerulosclerosis.
– Such progressive sclerosis may be initiated, at least in
part, by the adaptive changes that occur in the
remaining glomeruli not destroyed by the initial disease.
26
 Cont’d...

Podocyte injury.
27
 Nephrotic Syndrome
• A clinical complex that includes the following:
– (1) Massive proteinuria, with daily protein loss in the
urine of 3.5 gm or more in adults;
– (2) Hypoalbuminemia, with plasma albumin levels
less than 3 gm/dL;
– (3) Generalized edema, the most obvious clinical
manifestation; and
– (4) Hyperlipidemia and lipiduria.
 At the onset there is little or no azotemia,
hematuria, or hypertension.

28
Components of the Nephrotic Syndrome
• Initial event is a derangement in the capillary
walls of the glomeruli, resulting in increased
permeability to plasma proteins.
• With long-standing or extremely heavy
proteinuria, serum albumin is decreased,
resulting in hypoalbuminemia.
• Generalized edema of the nephrotic syndrome
– A consequence of the drop in plasma colloid osmotic
pressure as a result of hypoalbuminemia, and
– Primary retention of salt and water by the kidney.

29
 Cont’d...
• As fluid escapes from the vascular tree into
the tissues, there is a concomitant drop in
plasma volume, with diminished glomerular
filtration.
• Compensatory secretion of aldosterone, along
with the reduced GFR and reduction of
secretion of natriuretic peptides, promotes
retention of salt and water by the kidneys,
thus further aggravating the edema.
30
 Cont’d...
Fluid escapes from the vascular tree into the tissues

Drop in plasma volume, with diminished glomerular filtration.

Compensatory secretion of aldosterone

Retention of salt and water

Edema will be further aggravated

31
 Cont’d...
• Genesis of the hyperlipidemia is more obscure.
– Presumably, hypoalbuminemia triggers increased
synthesis of lipoproteins in the liver.
– There is also abnormal transport of circulating
lipid particles and impairment of peripheral
breakdown of lipoproteins.
– The lipiduria, in turn, reflects the increased
permeability of the GBM to lipoproteins.

32
 Relative frequencies of the several causes of
the nephrotic syndrome vary according to age
• In children 1- 7 years of age , it is almost always
caused by a lesion primary to the kidney.
• In adults it is often due to renal manifestations of a
systemic disease with the frequent systemic
causes being diabetes, amyloidosis, and SLE.
• Most important of the primary glomerular lesions
that characteristically lead to the nephrotic
syndrome are focal and segmental
glomerulosclerosis (FSGS) and minimal-change
disease (MCD).
33
 Systemic Diseases with Renal
Manifestations
• Diabetes mellitus
• Amyloidosis
• Systemic lupus erythematosus
• Ingestion of drugs (gold, penicillamine, "street
heroin")
• Infections (malaria, syphilis, hepatitis B, HIV)
• Malignancy (carcinoma, melanoma)
• Miscellaneous (bee-sting allergy, hereditary
nephritis)
34
 Minimal-change Disease (Lipoid
Nephrosis)
• The most frequent cause of the nephrotic
syndrome in children.
• Characterized by glomeruli that 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 ages 1-7
years.

35
 Pathogenesis
• Based on some experimental studies, the
proteinuria has been attributed to a T-cell
derived factor that causes podocyte damage
and effacement of foot processes.
• However, neither the nature of such a putative
factor nor a causal role of T-cells is established
in the human disease.

36
 Morphology
• With the light microscope, the glomeruli in minimal
change disease appear normal.
• Cells of the proximal convoluted tubules are often
heavily laden with protein droplets and lipids, but
this is secondary to tubular reabsorption of the
lipoproteins passing through the diseased glomeruli.
Lipoid nephrosis.
• Even with the electron microscope, the GBM
appears normal.
• The only obvious glomerular abnormality is the
uniform and diffuse effacement of the foot
processes of the podocytes.
37
 Clinical Course
• Insidious development of the nephrotic syndrome in
an otherwise healthy child.
• There is no hypertension, and renal function is
preserved in most individuals.
• The protein loss is usually confined to the smaller
serum proteins, chiefly albumin (selective proteinuria).
• The prognosis in children with this disorder is good.
• More than 90% of cases 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.
38
Focal and Segmental Glomerulosclerosis

• A lesion characterized histologically by:

– Sclerosis affecting some but not all
glomeruli (focal involvement) and
– Involving only segments of each affected
glomerulus.

39
 Cont’d...
• Can occur:
– (1) In association with other known conditions,
such as (HIV nephropathy, heroin nephropathy).
– (2) As a secondary event in other forms of GN (e.g.
IgA nephropathy).
– (3) As a maladaptation after nephron loss.
– (4) In inherited or congenital forms resulting from
mutations affecting cytoskeletal or related proteins
expressed in podocytes (e.g., nephrin); or
– (5) As a primary disease.
40
 Cont’d...
• Primary (or idiopathic) FSGS
– Accounts for approximately 20% to 30% of all cases of the
nephrotic syndrome.
– It is becoming an increasingly common cause of nephrotic
syndrome in adults and remains a frequent cause in children.
– In children it is important to distinguish this cause of the
nephrotic syndrome from MCD, because the clinical courses
are markedly different.
– Unlike MCD, there is a higher incidence of hematuria and
hypertension in persons with this lesion; their proteinuria is
nonselective, and in general their response to corticosteroid
therapy is poor.
– At least 50% of individuals with FSGS develop end-stage renal
failure within 10 years of diagnosis.
– Adults in general are even less well than children.
41
 Pathogenesis
• The pathogenesis of primary FSGS is unknown.
• Some investigators have suggested that FSGS and
MCD are part of a continuum and that MCD may
transform into FSGS.
• Others believe them to be distinct
clinicopathologic entities from the outset.
• In any case, injury to the podocytes is thought to
represent the initiating event of primary FSGS.
• As with MCD, permeability-increasing factors
produced by lymphocytes have been proposed.
42
 Morphology
• Affects only some of the glomeruli (hence the
term"focal") and initially only the juxtamedullary
glomeruli.
• Characterized by lesions occurring in some tufts
within a glomerulus and sparing of the others
(hence the term "segmental").
• Affected glomeruli exhibit increased mesangial
matrix, obliterated capillary lumens, and
deposition of hyaline masses (hyalinosis) and lipid
droplets.
43
 Cont’d...
• Immunofluorescence microscopy often reveals
nonspecific trapping of immunoglobulins, usually
IgM, and complement in the areas of hyalinosis.
• On electron microscopy, the podocytes exhibit
effacement of foot processes, as in MCD.
• Collapsing glomerulopathy
– Other variant, more severe manifestation.
– Collapse of the entire glomerular tuft and podocyte
hyperplasia.
– Poor prognosis

44
 Clinical Course
• There is little tendency for spontaneous
remission of idiopathic FSGS, and responses to
corticosteroid therapy are usually poor.
• Progression to renal failure occurs at varying
rates, and about 50% of individuals suffer
renal failure after 10 years.

45
 Membranous Nephropathy
(Membranous Glomerulonephritis)
• Slowly progressive disease, most common
between 30 and 50 years of age.
• Characterized morphologically by the presence
of subepithelial immunoglobulin-containing
deposits along the GBM.
diffuse thickening of the capillary wall.

46
 Cont’d...
• Membranous nephropathy is idiopathic in about 85% of
cases.
• In the remainder (secondary membranous
nephropathy), it may be secondary to other disorders,
including:
– (1) Infections (chronic hepatitis B, syphilis, schistosomiasis,
malaria);
– (2) Malignant tumors, particularly carcinoma of the lung
and colon and melanoma;
– (3) SLE and other autoimmune conditions;
– (4) Exposure to inorganic salts (gold, mercury); and
– (5) Drugs (penicillamine, captopril, nonsteroidal anti-
inflammatory agents).

47
 Pathogenesis
• A form of chronic immune complex nephritis.
• Most idiopathic forms are induced by antibodies
reacting in situ to endogenous or planted glomerular
antigens.
• Experimental model of membranous GN is Heymann
nephritis, which is induced in animals by immunization
with renal tubular brush border proteins.
– The antibodies that are produced react with an antigen
located in the GBM, resulting in granular deposits ("in situ
immune complex formation") and proteinuria without
severe inflammation.

48
 Morphology
• Light microscopy-the basic change in membranous
nephropathy appears to be diffuse thickening of the
GBM.
• Electron microscopy-subepithelial deposits that nestle
against the GBM and are separated from each other by
small, spike like protrusions of GBM matrix that form in
reaction to the deposits ("spike and dome" pattern).
• Podocytes show effacement of foot processes.
• Immunofluorescence microscopy shows typical
granular deposits of immunoglobulins and
complement along the GBM.

49
 Clinical Course
• Insidious development of the nephrotic syndrome,
usually without antecedent illness.
• Proteinuria is nonselective, with urinary loss of
globulins as well as smaller albumin molecules, and
does not usually respond to corticosteroid therapy.
• Proteinuria persists in over 60% of individuals 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.
50
 Membranoproliferative
Glomerulonephritis
• Manifested histologically by alterations in the
GBM and mesangium and by proliferation of
glomerular cells.
• Accounts for 5% to 10% of cases of idiopathic
nephrotic syndrome in children and adults.
• Some individuals present only with hematuria or
proteinuria in the non-nephrotic range; others
have a combined nephrotic-nephritic picture.

51
 Cont’d...
• Two major types of MPGN (I and II) are
recognized on the basis of distinct
ultrastructural, immunofluorescence
microscopic, and pathogenic findings.
• Of the two types, type I is far more common
(about 80% of cases).

52
 Pathogenesis
• Different pathogenic mechanisms are involved in
the development of type I and type II disease.
• Most cases of type I MPGN seem to be caused by
circulating immune complexes, akin to chronic
serum sickness, but the inciting antigen is not
known.
Type I MPGN also occurs in association with
hepatitis B and C antigenemia, SLE, infected
atrioventricular shunts, and extra-renal infections
with persistent or episodic antigenemia.
53
 Cont’d...
• The pathogenesis of type II MPGN, also known as
dense-deposit disease, is less clear.
The fundamental abnormality appears to be
excessive complement activation, which may be
caused by several mechanisms not involving
antibodies.
Some patients have an autoantibody against C3
convertase, called C3 nephritic factor, which is
believed to stabilize the enzyme and lead to
uncontrolled cleavage of C3 and activation of the
alternative complement pathway.

54
 Morphology
• Type I MPGN • Type II lesions
 Characterized by discrete  Deposition of material of
subendothelial electron- unknown composition, giving
rise to the term dense-
dense deposits. deposit disease.
 By immunofluorescence  C3 is present in irregular
microscopy, C3 is chunky and segmental linear
deposited in an irregular foci in the basement
granular pattern, and IgG membranes and in the
and early complement mesangium in characteristic
components (C1q and C4) circular aggregates (mesangial
rings).
are often also present.
 Ig G is usually absent, as are
the early components of the
classical complement
pathway (c1q and c4).
55
 Clinical Course
• The principal mode of presentation (in ∼50% of cases) is
the nephrotic syndrome, although MPGN may begin as
acute nephritis or mild proteinuria.
• The prognosis of MPGN is generally poor.
• Dense-deposit disease has a worse prognosis, and it
tends to recur in renal transplant recipients.
• Like many other GNs, MPGN, usually type I, may occur in
association with other known disorders (secondary
MPGN), such as SLE, hepatitis B and C, chronic liver
disease, and chronic bacterial infections.
• Indeed, many so-called idiopathic cases are believed to
be associated with hepatitis C and related
cryoglobulinemia.
56
 Nephritic Syndrome
• A clinical complex, usually of acute onset,
characterized by
– (1) Hematuria with dysmorphic red cells
and red blood cell casts in the urine,
– (2) Some degree of oliguria and azotemia,
and
– (3) Hypertension

57
 Cont’d...
• The lesions that cause the nephritic syndrome have
in common proliferation of the cells within the
glomeruli, accompanied by a leukocytic infiltrate.
• This inflammatory reaction injures the capillary
walls, permitting escape of red cells into the urine,
and induces hemodynamic changes that lead to a
reduction in the GFR.
• The reduced GFR is manifested clinically by oliguria,
reciprocal fluid retention, and azotemia.
• Hypertension is probably a result of both the fluid
retention and some augmented renin release from
the ischemic kidneys.
58
 Acute Postinfectious
(Poststreptococcal) Glomerulonephritis
• Typically caused by glomerular deposition of
immune complexes resulting in diffuse
proliferation and swelling of resident
glomerular cells and frequent infiltration of
leukocytes, especially neutrophils.
• The inciting antigen may be exogenous or
endogenous.
• The prototypic exogenous pattern is seen in
poststreptococcal GN.

59
 Cont’d...
• The classic case of poststreptococcal GN
develops in a child 1 to 4 weeks after the
individual recovers from a group A streptococcal
infection.
• Only certain "nephritogenic" strains of β-
hemolytic streptococci are capable of evoking
glomerular disease.
• In most cases the initial infection is localized to
the pharynx or skin.
60
 Pathogenesis
• Immune complex deposition is involved in the
pathogenesis of acute poststreptococcal GN.
• Typical features of immune complex disease,
such as hypocomplementemia and granular
deposits of IgG and complement on the GBM,
are seen.
• Relevant antigens are probably streptococcal
proteins, but their identity is not established.

61
 Morphology
• Light microscopy a fairly uniformly increased
cellularity of the glomerular tufts that affects
nearly all glomeruli, hence the term "diffuse“
• Electron microscopy shows deposited immune
complexes arrayed as subendothelial,
intramembranous, or, most often, subepithelial
"humps" nestled against the GBM.
• Immunofluorescence studies reveal scattered
granular deposits of IgG and complement
within the capillary walls.
62
 Clinical Course
• Abrupt onset, heralded by malaise, a slight
fever, nausea, and the nephritic syndrome.
• Oliguria, azotemia, and hypertension are only
mild to moderate.
• Some proteinuria is a constant feature of the
disease.
• Serum complement levels are low during the
active phase of the disease, and serum anti-
streptolysin O antibody titers are elevated in
poststreptococcal cases.
63
• Recovery occurs in most children in epidemic
cases.
• Some children develop rapidly progressive GN
due to severe injury with crescents or chronic
renal disease due to secondary scarring.
• In adults, 15% to 50% of individuals develop
end-stage renal disease over the ensuing few
years or 1 to 2 decades, depending on the
clinical and histologic severity.
• In contrast, in children, the prevalence of
chronicity after sporadic cases of acute
postinfectious GN is much lower.
64
 IGA Nephropathy (Berger Disease)
• 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.
• It is often associated with loin pain.
• IgA nephropathy is one of the most common
causes of recurrent microscopic or gross
hematuria and is the most common glomerular
disease revealed by renal biopsies worldwide.
65
• The pathogenic hallmark is the deposition of IgA
in the mesangium.
• Some have considered IgA nephropathy to be a
localized variant of Henoch-Schönlein purpura,
also characterized by IgA deposition in the
mesangium.
• In contrast to IgA nephropathy, which is purely a
renal disorder, Henoch-Schönlein purpura is a
systemic syndrome involving the skin (purpuric
rash), gastrointestinal tract (abdominal pain),
joints (arthritis), and kidneys.
66
 Pathogenesis
• Associated with an abnormality in IgA production
and clearance.
• IgA, the main immunoglobulin in mucosal
secretions, is at low levels in normal serum but
increased in 50% of patients with IgA nephropathy
due to increased production in the marrow.
• In addition, circulating IgA-containing immune
complexes are present in some individuals.
• Abnormality in glycosylation of the IgA
immunoglobulin, a process that would reduce
plasma clearance of IgA, thus favoring deposition in
the mesangium.
67
• IgA synthesis in response to respiratory or
gastrointestinal exposure to environmental
agents (e.g., viruses, bacteria, food proteins)
may lead to deposition of IgA and IgA-
containing immune complexes in the
mesangium, where they activate the
alternative complement pathway and initiate
glomerular injury.

68
 Clinical Course
• Most often affects children and young adults.
• More than half of those with IgA nephropathy
present with gross hematuria after an infection of
the respiratory or, less commonly, gastrointestinal
or urinary tract;
• 30% to 40% have only microscopic hematuria, with
or without proteinuria; and
• 5% to 10% develop a typical acute nephritic
syndrome.
• Slow progression to chronic renal failure occurs in
25% to 50% of cases during a period of 20 years.
69
 Hereditary Nephritis
• Refers to a group of hereditary glomerular
diseases caused by mutations in GBM proteins.
• The best-studied entity is Alport syndrome, in
which nephritis is accompanied by nerve
deafness and various eye disorders, including
lens dislocation, posterior cataracts, and
corneal dystrophy.

70
 Pathogenesis
• The GBM is largely composed of type IV
collagen, which is made up of heterotrimers
of α3, α4, and α5 type IV collagen.
• This form of type IV collagen is crucial for
normal function of the lens, cochlea, and
glomerulus.
• Mutation of any one of the α chains results in
defective heterotrimer assembly, and thus the
disease manifestations of Alport syndrome.

71
 Pathogenesis
• The GBM is largely composed of type IV
collagen, which is made up of heterotrimers
of α3, α4, and α5 type IV collagen.
• This form of type IV collagen is crucial for
normal function of the lens, cochlea, and
glomerulus.
• Mutation of any one of the α chains results in
defective heterotrimer assembly, and thus the
disease manifestations of Alport syndrome.

72
 Morphology
• Glomeruli in hereditary nephritis appear
unremarkable until late in the course.
• In some kidneys, interstitial cells take on a
foamy appearance as a result of accumulation
of neutral fats and mucopolysaccharides
(foam cells) as a reaction to marked
proteinuria.
• With progression, there is increasing
glomerulosclerosis, vascular sclerosis, tubular
atrophy, and interstitial fibrosis.
73
 Clinical Course
• Most commonly X-linked as a result of mutation
of the gene encoding α5 type IV collagen.
• Males therefore tend to be affected more
frequently and more severely than females and
are more likely to develop renal failure.
• Rarely, inheritance is autosomal recessive or
dominant, linked to defects in the genes that
encode α3 or α4 type IV collagen.
• Individuals with hereditary nephritis present at
age 5 to 20 years with gross or microscopic
hematuria and proteinuria, and overt renal failure
occurs between 20 and 50 years of age.
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• Female carriers of X-linked Alport syndrome or
carriers of either gender of the autosomal
forms usually present with persistent
hematuria, which is most often asymptomatic
and follows a benign course.
• In a few instances, a heterozygous defect in the
α3 or α4 chains is associated with persistent,
often familial hematuria and a benign course
(so-called benign familial hematuria, or thin
basement membrane lesion).

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 Rapidly Progressive (Crescentic)
Glomerulonephritis
• A clinical syndrome and not a specific etiologic
form of GN.
• Characterized by rapid and progressive loss of
renal function with features of the nephritic
syndrome, often with severe oliguria and (if
untreated) death from renal failure within weeks
to months.
• Histologic picture is characterized by the
presence of crescents (crescentic GN).
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 Pathogenesis
• In most cases the glomerular injury is
immunologically mediated.
• A practical classification divides CrGN into three
groups on the basis of immunologic finding.
• Although all three types of CrGN may be
associated with a well-defined renal or
extrarenal disease, in some cases CrGN is
idiopathic.

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• When the cause can be identified
– About 12% of individuals have anti-GBM
antibody-mediated GN (type I CrGN) with
or without lung involvement;
– 44% have type II CrGN; and
– The remaining 44% have pauci-immune
type III CrGN.
• All have severe glomerular injury.

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Anti-Glomerular Basement Membrane Antibody
(Type I) Crescentic Glomerulonephritis
• Characterized by linear deposits of IgG and, in
many cases, C3 on the GBM.
• Anti-GBM antibodies also bind to pulmonary
alveolar capillary basement membranes to
produce the clinical picture of pulmonary
hemorrhages associated with renal failure.
– These persons are said to have Goodpasture
syndrome.
• These individuals benefit from
plasmapheresis, which removes pathogenic
antibodies from the circulation.
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 Morphology
• Kidneys are enlarged and pale, often with petechial
hemorrhages on the cortical surfaces.
• Glomeruli show segmental necrosis and GBM
breaks, with resulting proliferation of the parietal
epithelial cells in response to the exudation of
plasma proteins including fibrin into Bowman's
space.
– These distinctive lesions of proliferation are called
crescents due to their shape as they fill Bowman's
space.

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• Immunofluorescence is characteristic with
strong linear staining of deposited IgG and C3
along the GBM.

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 Immune Complex-Mediated (Type II)
Crescentic Glomerulonephritis
• Immune complex-mediated disorders.
• Can be a complication of any of the immune
complex nephritides, including
– Poststreptococcal GN,
– SLE,
– IgA nephropathy, and
– Henoch-Schönlein purpura

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• Immunofluorescence studies reveal the
characteristic granular ("lumpy bumpy") pattern
of staining of the GBM and/or mesangium for
immunoglobulin and/or complement.
• These individuals cannot usually be helped by
plasmapheresis.

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 Morphology
• There is severe injury with segmental necrosis
and GBM breaks with resultant crescent
formation,
• In contrast to type I CrGN (anti-GBM antibody
disease), segments of glomeruli without necrosis
show evidence of the underlying immune
complex GN (e.g., diffuse proliferation and
leukocyte exudation in postinfectious GN or SLE,
and mesangial proliferation in IgA nephropathy or
Henoch-Schönlein purpura).
• Immunofluorescence shows the characteristic
granular pattern of the underlying immune
complex disease, and electron microscopy
demonstrates discrete deposits.
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 Pauci-Immune (Type III) Crescentic
Glomerulonephritis
• Lack of anti-GBM antibodies or significant
immune complex deposition detectable by
immunofluorescence and electron
microscopy.
• Most of these individuals have antineutrophil
cytoplasmic antibodies in the serum.
• In some cases type III CrGN is a component of
a systemic vasculitis such as microscopic
polyangiitis or Wegener granulomatosis.

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• In many cases, however, pauci-immune CrGN
is limited to the kidney and is thus called
idiopathic.

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 Morphology
• Glomeruli show segmental necrosis and GBM
breaks with resulting crescent formation.
• Uninvolved segments of glomeruli appear normal
without proliferation or prominent inflammatory
cell influx.
• However, in contrast to anti-GBM antibody disease,
immunofluorescence studies for immunoglobulin
and complement are negative or nearly so, and
there are no deposits detectable by electron
microscopy.
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 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 of these persons become
anuric and require long-term dialysis or
transplantation.
• The prognosis can be roughly related to the
number of crescents: those with crescents in less
than 80% of the glomeruli have a better prognosis
than those with higher percentages of crescents.
• Plasma exchange benefits some individuals,
particularly those with anti-GBM antibody GN and
Goodpasture syndrome. 88
 Chronic Glomerulonephritis
• It is an important cause of end-stage renal
disease presenting as chronic renal failure.
• Among all individuals who require chronic
hemodialysis or renal transplantation, 30% to
50% have the diagnosis of chronic GN.
• CrGNs, FSGS, MN, IgA nephropathy, and
MPGN.
• Usually first noted in young and middle-aged
adults.
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 Morphology
• Kidneys are symmetrically contracted and their
surfaces are red-brown and diffusely granular.
• Advanced scarring of the glomeruli, sometimes
to in the point of complete sclerosis.
Obliteration of the glomeruli is the end point
of many diseases.
• There is also marked interstitial fibrosis,
associated with atrophy and dropout of many
of the tubules in the cortex, and diminution
and loss of portions of the peritubular capillary
network.
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 Clinical Course
• Chronic GN develops insidiously and is
discovered only late in its course, after the
onset of renal insufficiency.
• Renal disease is first detected with the
discovery of proteinuria, hypertension, or
azotemia on routine medical examination.
• Transient episodes of either the nephritic or
the nephrotic syndrome.
• Hypertension is very common, and its effects
may dominate the clinical picture.
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• Without treatment, the prognosis is poor;
relentless progression to uremia and death is
the rule.
• The rate of progression is extremely variable,
however, and 10 years or more may elapse
between onset of the first symptoms and
terminal renal failure.
• Renal dialysis and kidney transplantation, of
course, alter this course and allow long-term
survival.

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 References
• 1.Robbins Basic Pathology 9th edition
• 2.General and systemic pathology, 4th edition

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THANK YOU

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