Kidney disease pathophysiology with its type nephrotic and nephritic and applied

1. GLOMERULONEPHRITIS

2. GLOMERULAR DISEASES
Glomerular disease includes glomerulonephritis, i.e. inflammation of the
glomeruli and glomerulopathies when there is no evidence of
inflammation.Glomerular diseases consist a large and clinically
significant group of renal diseases.
Glomerulonephritis is the term used for diseases that primarily involve
the renal glomeruli.
It is classified into 2 broad groups:-
1. PRIMARY GLOMERULONEPHRITIS (the disease affects kidney only)
2. SECONDARY GLOMERULAR DISEASES (the disease affects kidney and
other organs)
3. Hereditary nephritis

3. Glomerulus , the filtering unit of the kidney

5. Possible Clinical Manifestations
Following are the six major glomerular syndromes commonly found
in different glomerular disease:-
1. Nephritic syndrome
2. Nephrotic syndromes
3. Acute renal failure
4. Chronic renal failure
5. Asymptomatic proteinuria
6. Haematuria

6. I. Acute Nephritic Syndrome
Onset of
a) Haematuria
b) Proteinuria (less than 3gm per 24hrs)
c) Hypertension
d) Oedema
e) Oliguria

7. II. Nephrotic Syndrome
Characterised by findings of massive
a) Heavy proteinuria (more than 3gm per 24hrs)
b) Hypoalbuminaemia
c) Oedema
d) Hyperlipidaemia
e) Lipiduria
f) Hypercoagulability

9. PRIMARY GLOMERULONEPHRITIS
Glomerulonephritis refers to an inflammation of the glomerulus, which is the
unit involved in filtration in the kidney. This inflammation typically results in
one or both of the nephrotic or nephritic syndromes.
In 1872, Klebs coined the term “glomerulonephritis”

10. Classification Of Primary Glomerulonephritis
ACUTE GN
1. Post streptococcal
2. Non streptococcal
RAPIDLY PROGRESSIVE GN
MINIMAL CHANGE DISEASE
MEMBRANOUS GN
MEMBRANO-PROLIFERATIVE GN
FOCAL PROLIFERATIVE GN
FOCAL SEGMENTAL GLOMERULEROSIS
IgA NEPHROPATHY
CHRONIC GLOMERULONEPHRITIS

11. 1.ACUTE GLOMERULONEPHRITIS
(Acute diffuse proliferative GN, diffuse endocapillary GN)
Acute Glomerulonephritis is characterised by the presence of acute
nephritic syndrome.
Based on etiologic agent, acute GN is subdivided into 2 main groups:-
1. Acute post-streptococcal GN
2. Acute non-streptococcal GN

12. ACUTE POST STREPTOCOCCAL GN
Acute post streptococcal glomerulonephritis is an immunologic response of the kidney to infection,
characterized by the sudden appearance of edema, hematuria, proteinuria and hypertension
INCIDENCE
Classic example of the acute nephritic syndrome.
a) Common form of GN in developing countries.
b) Uncommon in the western countries.
c) Mostly affecting children between 2-14 years (early school ages)
d) 10% cases are seen in adults above 40 years
e) Male to female ratio is 2:1

13. Etiology
PSGN follows infection of the throat or skin by certain
“nephritogenic” strains of Group A Beta haemolytic streptococci.
More than 90% of cases being traced to type 12,4 and 1, which can
be defined by typing
of M protein of the cell wall.
Nephritogenic strains
Pharyngitis associated -1, 3, 4, 12
Skin infection associated-2, 49 ,55, 57 and 60

14. Onset of disease is generally sudden after
1-2 weeks of throat infection
(e.g. streptococcal pharyngitis)
3-6 weeks after skin infection(impetigo)
(e.g. streptococcal impetigo)

15. Risk Factors
Poor hygiene
Overcrowding
Low socioeconomic status
Genetic factors are expected to predispose to the condition since almost
40% of patients with PSGN gave a positive family history. There is no
specific gene found to cause PSGN.

16. Pathogenesis
PSGN is an immune mediated disease.
The child gets throat or skin infection by nephritogenic strain of group A beta
haemolytic streptococci.
And these bacteria release toxin streptolysin.
Antigens of the bacteria initiate an immune response due to which antibodies
to streptococcus (eg antistreptolysin O, anti streptokinase) are formed in the
circulation.
And then antigen and antibody form the antigen antibody complex.
Antigen antibody circulating immune complexes are subsequently deposited
along the glomerular basement membrane(GBM), which results into glomerular
damage.

18. There is another mechanism which can also lead to glomerular
damage is when the antibody directly damage the glomerulus , this is
because the antibody produce in response to streptococcal antigen
mimics the glomerulus antigen.(Because of the similarity between
glomerular and streptococcal antigens) i.e, SPEB protein and M
protein.
Antibody were produced to damage the streptococcal antigen but
instead of destroying antigen ,these antibody cross-react with
glomerulus protein, which evoked autoimmunity which leads to
glomerulus damage and this type of mimic is known as MOLECULAR
MIMICRY.
When there is immune complex deposition on the glomerulus, it
leads to the activation of complement system, which leads to
inflammation.
After the glomerular damage , there is the leak in glomerulus which
causes haematuria and proteinuria.

19. Streptococcal infection
immune complex formation+deposited in GBM
complement system activated
immune injuries
cellular proliferation GBM fracture
capillary lumen narrowed haematuria
glomerular blood flow decreased proteinuria
oliguria GFR distal sodium reabsorption
hypoalbuminaemia
retention of water and sodium
blood volume
edema
hypertension

21. Morphological Features
Kidneys are symmetrically enlarged, weighing
one and a half to twice the normal weight .
Presence of haemorrhages giving the characteristics
appearance of flea bitten kidney .
Light microscopic findings
Early stage → glomerular hypercellularity
Later stage → Proliferation of intrinsic endothelial & mesangial cells
Electron microscopic findings
Characteristic electron dense irregular deposits(humps) on the epithelial side
of the GBM.
Immunofluorescence microscopy
Starry sky,Irregular deposits along the GBM consist principally of IgA and
complement C3.
Flea bitten
kidney

23. Clinical Features
•Puffness of face-in the morning
• Edema feet
•in the classic case,a young child abruptly develops
malaise,fever,nausea,oliguria and,hematuria(smoky or cola coloured
urine) 1 to 2 weeks after recovery from a sore throat.
•A patient can have red cell casts in the urine,mild proteinuria(less the
3 gm /24 hrs),Hypertension, periorbital oedema and variably
oliguria.
•In adults, the features are atypical and include sudden hypertension,
oedema .
•Children almost always (95%) recover completely.

25. Complications
Hyper tensive encephalopathy
failure of autoregulatory system of the vessels of the brain due to acute rise of blood
pressure
Heart failure
Hypocalcaemia
Rapidly progressive GN
Chronic GN
Uraemia
Chronic renal failure
Pulmonary edema

26. ACUTE NON-STREPTOCOCCAL GN
1/3rd cases of Acute GN
Caused by organism other than haemolytic streptococci which includes
a) Bacteria (e.g. staphylococci, pneumococci, meningococci, salmonella
and pseudomonas)
b) Viruses (e.g. hepatitis B virus, mumps, infectious mononucleosis and
varicella)
c) Parasitic infections(e.g. malaria,toxoplasmosis and schistosomiasis)
d) syphilis

27. 2.RAPIDLY PROGRESSIVE
GLOMERULONEPHRITIS
(RPGN, CRESENTIC GN, EXTRACAPILLARY GN)
The term Rapidly progressive glomerulonephritis (RPGN) refers to a clinical
syndrome characterized by a rapid loss of kidney function(GFR>50%)from a few
days to weeks,RPGN is characterized by the presence of crescents (crescentic GN)
and in most cases appears to be immunologically mediated.
It is the result of focal rupture of glomerular capillary walls that allows
inflammatory mediators and leukocytes to enter Bowman’s space, where they
induce epithelial cell proliferation and macrophage influx and maturation that
together produce cellular crescents.
• It is a clinical syndrome
• RPGN is characterized by rapid loss of renal function
• laboratory findings typical of the nephritic Syndrome
• severe oliguria
• If untreated, it can rapidly lead to renal failure within a period of weeks to
months.

28. Etiology
Infection diseases
• Post-streptococcal GN
• Infectious endocarditis
Idiopathic
• Type 1: Antiglomerular basement membrane antibody disease
• Type 2: immune complex-mediated disease
• Type 3: pauci-immune(ANCA- associated) disease

29. Multisystemic diseases
• Systemic lupus erythematosus
• Goodpasture’s disease
• Henoch-Schonlein purpura
• Necrotizing vasculitis (including Wegener’s gransulomatosis.
Superimposed on primary glomerular disease
• Membranoproliferative GN (type I, I1)
• Membranous GN Wegener’s
• IgA nephropathy

30. CLASSIFICATION OF RPGN
Type 1- Anti glomerular basement membrane Disease
Type 2-Immune complex disease
Type 3-Pauci immune disease ANCA

31. TYPE 1- ANTI-GBM ANTIBODY MEDIATED
CRESENTRIC GN
(Goodpasture’s disease )
•Characterized by linear deposits of IgG and C3 in the GBM.
•In some patients, the Anti-GBM antibodies also bind to pulmonary
alveolar capillary basement membranes to produce the clinical picture
of pulmonary hemorrhages associated with renal failure( these
patients are said to have Goodpasture Syndrome).
•Anti-GBM antibodies are present in the serum.

32. Pathogenesis
•Due to autoimmune disorder composition of basement membrane
acts as antigen .
(Antigen present at Non collagenous domain (NC1)of the alpha -3
chain of type (IV) collagen in the glomerular basement membrane)
•Antibodies will form in the lumen of the capillaries and move to
basement membrane.
•Antigen antibody immune complex formation in GBM with c
complement.
•React with GBM and alveolar BM and causes immune complex
disease such as rapidly progressive glomerulonephritis and vasculitis.

34. TYPE 2-IMMUNE COMPLEX-MEDIATED
CRESCENTRIC GN
May complicate any of the immune complex nephritides, including
1.Primary glomerulonephritis
• IgA nephropathy
• Post-infectious glomerulonephritis
• MPGN
2.Secondary glomerulonephritis(systemic)
• SLE
• Cryoglobulinemia
• IgA vasculitis(HSP)
• Immune complex-mediated GN accounts for the majority in children but for
only a minority in older adults.

35. This type of RPGN frequently shows cellular proliferation and influx of
leucocytes within the glomerular tuft, in addition to cres-cent
formation.

37. TYPE 3-PAUCI IMMUNE DISEASE ANCA
•Is defined by ANCA (Anti neutrophilic cytoplasmic antibodies
associated immune disease lack of anti gbm antibodies or immune
complex deposition With little or no glomerular staining for
immunoglobulins by immunofluorescence microscopy.
•Pauci-immune crescentic glomerulonephritis usually is a component
of a systemic small vessel vasculitis such as microscopic polyangiitis
or granulomatosis with polyangitis is the most common category of
RPGN in adults .

38. PATHOGENES
IS

39. MORPHOLOGY
Grossly
•the kidneys are usually enlarged and pale with smooth outer surface
(large white kidney). Cut surface shows pale cortex and congested
medulla.

40. 1.Light microscopy
Vary according to the cause but in general, following
Glomeruli
•All forms of RPGN show pathognomonic ‘crescents’ on the inside of
Bowman’s capsules.
•Crescents obliterate the Bowman’s Space and compress the
glomerular tuft
•Fibrin deposition present in bowman’s capsule
•Glomerular tufts may show increased cellularity due to proliferation
of endothelial and mesangial cells and leucocytic infiltration

41. Tubules
•Tubular epithelial cells may show hyaline droplets.
•lamina may contain casts, red blood cells and fibrin.
Interstitium
•The interstitium is edematous and may show early fibrosis.
• lymphocytes and plasma cells, are distributed in the interstitial
tissue.
Vessels
•Arteries and arterioles may show no change, but cases associated
with hypertension usually show severe vascular changes.

43. 2. Immunofluorescence microscopy
Vary according to the type of RPGN
Immune complex mediated RPGN show subepithelial granular
deposits similar to those seen in acute GN.
While RPGN in Goodpasteur’s syndrome show characteristic linear
deposits along GBM.
3.Electron microscopy
1.linear pattern of RPGN in Goodpasture’s syndrome (type I RPGN),
contain IgG and C3 along the Capillaries.
2.Granular pattern of post-infectious RPGN (type II RPGN) Consisting
of IgG and C3 along the capillary wall.
3. Scanty or no deposits of immunoglobulin and C3 in Pauci-immune
GN (type III RPGN)

44. ANTI-
GBM
IMMUNE COMPLEX
MEDIATED
IMMUNOFLUORESCENCE
MICROSCOPY

45. Clinical Features
•Acute nephritic syndrome.
•Oliguria and azotemia.
•Proteinuria sometimes approaching the nephrotic range may occur.
•Some individuals become anuric and require long-term dialysis or
transplantation.
•Acute renal failure and intrapulmonary haemorrhage
•The Prognosis is roughly predicted by the fraction of involved Glomeruli, as
patients in whom crescents are present in less than 80% of the glomeruli have a
more favorable prognosis than those in whom the percentage of crescents is
higher.
•Plasma exchange may be of benefit in those with anti-GBM Antibody GN and in
some cases of ANCA-related pauci-Immune crescentic GN.

47. MINIMAL CHANGE DISEASE
Minimal-change disease, a relatively benign disorder, is the most
frequent cause of the nephrotic syndrome in children and is
characterized by glomeruli that have a normal appearance by light
microscopy.
•Diffuse effacement of podocyte foot processes is seen with
electron microscopy.
most common between 1 and 7 years of age.

48. Pathogenesis
•some circulating molecules injure podocytes and cause proteinuria with
effacement of foot Processes
•Absence of deposits by immunofluorescence microscopy.
•Normal circulating levels of complement but presence of Circulating immune
complexes in many cases.
•Universal satisfactory response to steroid therapy.
•Evidence of increased suppressor T cell activity with elaboration of cytokines
(interleukin-8, tumour necrosis factor) Which probably cause foot process
flattening and altered
•Nephrotic syndrome in MCD in children is characterised by selective
proteinuria containing mainly albumin, and minimal amounts of
macroglobulin.

49. •basis for selective proteinuria appears to be as under:
1-Reduction of normal negative charge on GBM due to loss of
heparan sulfate proteoglycan from the GBM.
2-Change in the shape of epithelial cells producing foot process
flattening due to reduction of sialoglyco protein cell coat.
Adults having MCD, however, have non-selective proteinuria,
suggesting more extensive membrane permeability defect.

51. Morphology
Grossly, the kidneys are of normal size and shape.
LIGHT MICROSCOPY
Glomeruli
No abnormality in the glomeruli
Tubules
presence of fine lipid vacuolation and hyaline droplets in the cells of PCT and,
hence, the older name of the condition as ‘lipoid nephrosis’.
Interstitium
There may be oedema of the interstitium
Vessels
Blood vessels do not show any signifiant Change.

53. ELECTRON MICROSCOPY
•GBM appears normal and no electron dense material is deposited
•Principal lesion-visceral epithelial cells show uniform diffuse
effacement of foot processes and cytoplasm with loss of recognisable
intervening slit diaphragms
•Such change can be seen in the diseases also like membranous
glomerulopathy or DM
•Cells of proximal tubules are laden with lipids and protein reflecting
tubular reabsorption of lipoproteins passing through diseased
glomeruli-thus the historical name is lipoid nephrosis
IMMUNOFLUORESCENCE STUDIES
No immunoglobulin or complement deposits

54. Clinical Features
•fully-developed nephrotic syndrome with massive and highly
selective proteinuria
•hypertension
• preeceded by an upper respiratory Infection, atopic allergy or
immunisation.
•The disease characteristically responds to steroid therapy.
•In long-term prognosis is Very good and most children become
free of albuminuria after Several years.

55. MEMBRANOUS NEPHROPATHY
Membranous nephropathy is characterized by subepithelial immunoglobulin
containing deposits along the GBM and widespread thickening of glomerular capillary
wall.
•It is the most common cause Of nephrotic syndrome in adults between the ages of
30 and 60 years
•Up to 80% of cases of membranous nephropathy are Primary, caused by
autoantibodies against podocyte antigens
•it occurs secondary to other Conditions, including the following:
1- Infections (chronic hepatitis B, syphilis, and ,Malaria)
2-Malignant neoplasms, particularly carcinoma of the lung and colon and melanoma
3-Autoimmune diseases, particularly systemic lupus erythematosus
4-Exposure to inorganic salts (gold, mercury)
5-Drugs (penicillamine, captopril, nonsteroidal anti-Inflammatory agents)

56. Pathogenesis
Membranous nephropathy is a form of chronic immune Complex
glomerulonephritis induced by antibodies reactIng in situ to
endogenous or planted glomerular antigens.
•Antibodies against the podocyte antigen phospholipase A2 Receptor
(PLA2R) are frequently present but it is not established that they are
causative
•Formation of subepithelial Immune deposits leads to complement
activation on the Surface of podocytes and generates the membrane
attack Complex (C5-C9)
•This in turn causes podocyte injury and Proteinuria.

58. Morphology
GROSS
The kidneys are enlarged ,pale and smooth.
LIGHT MICROSCOPY
shows the following findings
Glomeruli
• diffuse thickening of the glomerular capillary walls with all the glomeruli being
affected
•As the disease progresses, thickened basement membrane, producing
‘duplication’ of GBM which is actually formation of a new basement membrane
•The basement membrane changes are best appreciated by silver impregnation
stains (black colour) or by periodic acid-Schiff stain (pink colour)
•There is no cellular proliferation in the glomerular tufts.

59. Tubules
•The renal tubules remain normal except in the early stage when
lipid vacuolation of the proximal tubules may be seen
Interstitium
•The interstitium may show fine fibrosis and scanty chronic
inflammatory cells
Vessels
•In the early stage, vascular changes are not prominent, while later
hypertensive changes of arterioles may occur.

60. Electron
microscopy
Light
microscopy
Immunofluorescence
microscopy

61. ELECTRON MICROSCOPY
•shows characteristic electron-dense deposits in subepithelial
location.
• The basement membrane material protrudes between deposits as
‘spikes’
IMMUNOFLUORESCENCE MICROSCOPY
•reveals granular deposits of immune complexes consisting of IgG
associated with complement C3
•In secondary cases of membranous GN the relevent antigen such as
hepatitis B or tumour antigen may be seen

62. Clinical Features
• full-blown nephrotic syndrome.
•proteinuria is usually of non-selective type.
•microscopic haematuria and hypertension may be present at the
onset.
•The changes in membranous GN are irreversible in majority of
patients.
•Progression to impaired renal function and end stage renal disease
with progressive azotemia occurs in approximately 50% cases within
a span of 2 to 20 years.
•Renal vein thrombosis due to hypercoagulability.

63. MEMBRANE PROLIFERATIVE GN
•Membranoproliferative GN is another important cause of nephrotic
syndrome in children and young adults.
•As the name implies, it is characterised by two histologic features
1) Increase in cellularity of the mesangium associated with increased
lobulation of the tuft.
2) Irregular thickening of the capillary wall

64. Etiopathogenesis
Etiology of MPGN is unknown though in some cases there is evidence of
preceding streptococcal infection.
Based on ultrastructural, immunofluorescence and pathogenetic
mechanisms, three types of MPGN are recognised:
Type I or Classic form
It is an example of immune complex disease and comprises more than
70% cases. It is characterised by immune deposits in
the subendothelial position. Immune-
complex MPGN is seen in association with
1) Systemic Immune Complex diseases (e.g. SLE etc)
2) Chronic infections (e.g. HIV, hepatitis B and C) and,
3) Malignancies (e.g. lymphomas and leukaemias)

65. Type Il or dense deposit disease
•It is the example of alternative pathway disease and constitutes
about 30% cases.
•The capillary wall thickening is due to the deposition of electron-
dense material in the lamina densa of the GBM.
•Type II MPGN is an autoimmune disease in which patients have IgG
autoantibody termed C3 nephritic factor.
•Type II cases have an association with partial
lipodystrophy,characterised by symmetrical loss of subcutaneous fat
from the upper half of the body.
Type III
It is rare and shows features of type I MPGN and membranous
nephropathy in association with systemic diseases or drugs.

66. Morphological Features
Grossly, the kidneys are usually pale in appearance and firm in
consistency.
By light microscopy, the features are as under:-
•Glomeruli show highly characteristic changes.
•They are enlarged with accentuated lobular pattern.
•The enlargement is due to variable degree of mesangial cellular
proliferation and increase in mesangial matrix.
•The GBM is considerably thickened; with silver stains it shows two
basement membranes with a clear zone between them.
•This is commonly referred to as Double contour, splitting, or 'tram track'
appearance.

68. Clinical Features
•The most common age at diagnosis is between 15 and 20 years.
•Approximately 50% of the patients present with nephrotic syndrome; about
30% have asymptomatic proteinuria; and 20% have nephritic syndrome at
presentation.
•The proteinuria is non-selective. Haematuria and hypertension are
frequently present.
•With time, majority of patients progress to renal failure, while some
continue to have proteinuria, haematuria and hypertension with stable
renal function.
•Prognosis of type I is relatively better and majority of patients survive
without clinically significant impairment of GFR, while type II cases run a
variable clinical course.

69. FOCAL PROLIFERATIVE GN
Focal proliferative GN is characterised by pathologic changes in
fewer than 50% glomeruli (focal), often confined to one or two
lobules of the affected glomeruli while other glomeruli are
normal.

70. Etiopathogenesis
It may occur under following diverse clinical setting
i) As an early manifestation of a number of systemic diseases such as
SLE,subacute bacterial endocarditis and polyarteritis nodosa,
Goodpasture's syndrome.
ii) As a component of a known renal disease such as in IgA
nephropathy.
iii) As a primary idiopathic glomerular disease unrelated to systemic or
other renal disease.
The observation of mesangial deposits of immunoglobulins and
complement suggest immune complex disease and participation of the
mesengium.

71. Morphological Features
BY LIGHT MICROSCOPY
The single most important feature in focal GN is the abnormality seen
in certain number of glomeruli and generally confined to one or two
lobules of the affected glomeruli i.e. focal and segmental glomerular
involvement.
The pathologic change most frequently consists of focal and
segmental cellular proliferation of mesangial cells and endothelial
cells but sometimes necrotising changes can be seen.
BY IMMUNOFLUORESCENCE MICROSCOPY
Widespread mesangial deposits of immunoglobulins (mainly IgA with
or without IgG), complement (C3) and fibrin are demonstrated in
most cases of focal GN.

73. Clinical Features
•The clinical features vary according to the condition causing it.
•Haematuria is one of the most common clinical manifestation.
•Proteinuria is frequently mild to moderate but hypertension is
uncommon

74. FOCAL SEGMENTAL
GLOMERULOSCLEROSIS
•Also known as Focal Sclerosis, Focal Hyalinosis
•Focal segmental glomerulosclerosis (FSGS) is a condition in which
there is sclerosis and hyalinosis of some glomeruli and portions of
their tuft (less than 50% in a tissue section), while the other glomeruli
are normal by light microscopy i.e. involvement is focal and
segmental.

75. Sclerosis of-
•Some, but not all,glomeruli (thus,it is focal)
•In the affected glomeruli,only a portion of capillary tuft is involved
(thus,it is semental)

76. Causes
PRIMARY FSGS
•Occurs on its own
•Genetics
•Kidney failure
SECONDARY FSGS
Kidney defects from birth
Kidney reflux
Obesity
HIV
Diabetes mellitus
Heroine abuse

77. Diagnosis
CLINICAL TESTS
Urinalysis
Blood tests
Kidney biopsy

78. Light Microscopy
•Depending upon the severity of the disease, variable number of
glomeruli are affected focally and segmentally, while others are
normal.
•The affected glomeruli show solidification or sclerosis of one or more
lobules of the tuft.
•Hyalinosis refers to collection of eosinophilic,homogeneous, PAS-
positive, hyaline material present on the inner aspect of a sclerotic
peripheral capillary loop.

80. Electron Microscopy
Diffuse loss of foot processes as seen in minimal change disease is
evident but, in addition, there are electron-dense deposits in the
region of hyalinosis and sclerosis which are believed to be immune
complexes.

81. IgA NEPHROPATHY
•Also known as Berger's Disease, IgA GN.
•It is the most common type of glomerulonephritis world wide.
•It is characterised by aggregates of IgA, deposited principally in the
mesangium.
•The condition was first described by Berger, a French physician in 1968.
•Children and young adults are commonly affected.
•It occurs after an upper respiratory tract infection or gastrointestinal
infection.

82. Pathogenesis
In view of exclusive mesangial deposits of IgA and elevated serum
levels of IgA and IgA-immune complexes, IgA nephropathy has been
considered to arise from entrapment of these immune complexes
from circulation in the mesangium.
Presence of C3 and properdin in the mesangial deposits point
towards activation of alternate complement pathway.
HLA-B35 association has been reported in some cases→possibility of
genetically-determined abnormality of the immune system producing
an ease in circulating IgA.

83. Causes
Body produces abnormal IgA proteins
•Body recognizes as foreign
•Reason is unknown
•Genetic factors play a role.

84. Light Microscopy
Various patterns
•Focal proliferative GN
•Focal segmental glomerulosclerosis
•Membranoproliferative GN
•Rarely RPGN

85. Electron Microscopy
Finely granular electron-dense deposits are seen in the
mesangium.

86. Immunofluorescence Microscopy
 Mesangial deposits of IgA, with or without IgG, and usually
with C3 and properdin.

87. Clinical Features
•Nephritic syndrome
•Occasionally nephrotic syndrome

88. CHRONIC GLOMERULONEPHRITIS
Also known as End-stage kidney, Chronic kidney disease.
Chronic GN is the final stage of a variety of glomerular diseases which
result in irreversible impairment of renal function.
i) Rapidly progressive GN (90%)
ii) Membranous GN (50%)
iii) Membranoproliferative GN (50%)
iv) Focal segmental glomerulosclerosis (50%)
v) IgA nephropathy (40%)
vi) Acute post-streptococcal GN (1%).

89. GROSSLY
 The kidneys are usually small and contracted weighing as low as 50 gm
each.
 The capsule is adherent to the cortex.
 The cortical surface is generally diffusely granular.
 On cut section the cortex is narrow and atrophic, while the medulla is
unremarkable.

90. Light Microscopy
GLOMERULI
Glomeruli are reduced in number.
Show completely hyalinized tufts , giving appearance of acellular,
eosinophilic masses which are PASpositive.
Evidence of underlying glomerular disease may be present.
TUBULES
Many tubules completely disappear and there may be atrophy of tubules
close to scarred glomeruli.
Tubular cells show hyaline-droplets, degeneration and tubular lumina
frequently contain eosinophilic, homogenous casts.

92. SECONDARY SYSTEMIC GLOMERULAR DISEASES
Secondary glomerular diseases are kidney conditions with glomerular
pathology in which an underlying cause can be established.
1. Lupus nephritis (SLE)
2. Diabetic nephropathy
3. Amyloidosis
4. Polyarteritis nodosa
5. Wegener’s granulomatosis
6. Good pasteur syndrome
7. Henoch-schonlein purpura
8. Systemic infectious diseases
9. Idiopathic mixed cryoglobulinaemia

93. SYSTEMIC LUPUS ERYTHEMATOSUS
WHAT IS SLE?
Systemic lupus erythematosus is a chronic,
multisystem, inflammatory, autoimmune disorder
characterized by formation of autoantibodies directed
against self-antigens and immune-complex formation
resulting in damage to essentially any organ.

94. EPIDEMIOLOGY
Although SLE affects primarily women of childbearing age,
approximately 5% of cases present in childhood, mainly around
puberty. SLE is rare in children younger than 9 years of age. Although
there is a female predominance of this disease and adulthood, there
is an equal gender distribution in children. The overall prevalence of
SLE in pediatric population is 10 to 25 cases per 100,000 children.

95. TYPES OF LUPUS
1. Systemic Lupus Erythematosus(SLE)
One that most people refer to when they say “lupus”. The
symptoms of SLE may be mild or serious . Although SLE usually
first affects people between the ages of 15 and 45 it occur in
childhood or later in life as well.

96. 2 Discoid Lupus Erythematosus(DLE)
A chronic skin disorder in which a red, raised rash appears on
the face, scalps, or elsewhere. The raised area may become
thick and scalp may cause scarring. The rash may last for days
or years and may recur. A small percentage of people with
discoid lupus have or develop SLE later.

97. 3. Neonatal Lupus
A rare disorder that can occur in newborn babies. Scientists
suspect that neonatal lupus is caused by auto-antibodies in the
mothers blood called anti-Ro (SSA) and anti-La (SSB). Auto-
antibodies are blood proteins that act against body own part.

98. What Causes SLE?
•SLE is an autoimmune disorder that develops when the body
attack to its own tissues. Its causes is unknown, but it is likely
that a combination of genetic, environmental, and possibly,
hormonal factors work together to cause SLE.
•This occurs through the production of “auto-antibodies” that
attack a person own cell thus contributing to the inflammation
of various part of body and may cause damage to organ and
tissues.
•The most common type of auto-antibodies are antinuclear
antibody(ANA) because it react with parts of cell
nucleus(command centre)

99. •Fact that SLE can run in families indicates that its
development has a genetic basis;however no specific
“lupus gene” has been identified yet.
•Some studies say sunlight, stress, certain
drug(hydralazine,quinine etc) and agents such as
virues(human endogenous retrovirus,cytomegalovirus).

100. Diagnosis
1 Malar rash – rash over cheek & nose
often in shape of butterfly.
2 Discoid rash – red, raised, disk-shaped patches.
3 Photosensitivity .
4 Oral ulcer – sore appear in mouth.
5 Arthritis.
6 Kidney disorder – protein or cellular cast in urine.
7 Abnormal antinuclear antibody (ANA)

101. Cardiac Manifestation Of SLE
•Pericarditis
•Myocarditis, congestive heart failure
•Hypertension
•Coronary vasculitis
•Libman-Sacks endocarditis
•Valvular insufficiency
•SLE patients have a 7–10x increased risk of coronary heart disease
and stroke

102. Neuropsychiatric Manifestations Of SLE
Central nervous system
 Diffuse cerebral manifestations
 Psychiatric manifestations (depression)
 Cognitive impairment
 Seizures
 Headache
 Focal manifestations
Peripheral nervous system

103. Pulmonary Manifestations Of SLE
•Pleuritis (also pericarditis)
•Susceptibility to infection
•Lupus pneumonitis/alveolitis
•Pulmonary hemorrhage
•Pulmonary fibrosis
•Pulmonary hypertension

104. Complications
•Hypertension
•Growth retardation
•Chronic pulmonary impairment
•Permanent renal damage

105. DIABETIC NEPHROPATHY
Persistent albuminuria (>3g/day ) is the hallmark of diabetic
nephropathy.
Clinically, diabetic nephropathy is characterized by a
progressive increase in proteinuria and decline in GFR,
hypertension, and a high risk of cardiovascular morbidity and
mortality.

106. Incidence
•Approximately 40% of patients with types 1 or 2 diabetes develop
nephropathy, but due to the higher prevalence of type 2 diabetes
(90%) compared to type 1 (10%), the majority of patient with diabetic
nephropathy have type 2 disease.
•Microalbuminuria appears 5–10 years after the onset of diabetes.
• It is currently recommended to test patients with type 1 disease for
microalbuminuria 5 years after diagnosis of diabetes and yearly
thereafter and, to test type 2 patients at the time of diagnosis of
diabetes and yearly thereafter.

107. Pathogenesis
Within 1–2 years after the onset of clinical diabetes,
morphologic changes appear in the kidney.
Thickening of the GBM is a sensitive indicator for the presence
of diabetes but correlates poorly with the presence or absence
of clinically significant nephropathy.
Afferent and efferent glomerular arteriolar hyalinosis can also
be detected within 3 to 5 years after onset of diabetes.

108. Renal extracellular membranes, including GBM, TBM and
Bowman’s capsule, demonstrate increased intensity of
immunofluorescent linear staining for plasma proteins,
especially albumin and immunoglobulin G .
Because these changes are seen in all diabetic patients and
appear unrelated to disease risk, their only clinical importance
is that they should not be confused with other entities, such as
anti- GBM antibody disorders.

109. Microalbuminuria
Urinary albumin excretion within the microalbuminuric range (30 mg to 300
mg/24 hr) in at least two out of three consecutive nonketotic sterile urine
samples is definied as persistent microalbuminuria.
Urinary albumin/creatinine ratio is measured, and microalbuminuria is defined
as 30 to 300 mg/g creatinine.
Factors causing microalbuminuria are
1. Loss of glomerular charge selectivity
2. Changes in podocyte number and morphology.
3. Elevated filtration both at rest and during exercise compared with normal
controls
4. Glomerular hypertension with or without systemic hypertension.

110. DIABETIC NEPHROPATHY
Diabetic nephropathy is a clinical syndrome characterized by
1. Persistent albuminuria (>300 mg/24 hr, or 300 mg/g
creatinine).
2. A decline in GFR.
3. Raised arterial blood pressure.
4. Enhanced cardiovascular morbidity and mortality.

111. Albuminuria is the first sign, peripheral edema is often the first
symptom of diabetic nephropathy.
Fluid retention is frequently observed early in the course of this
kidney disease; that is, at a stage characterized by well preserved
renal function and only a modest reduction in serum albumin level.
Rate of decline in GFR is highly variable across individuals, ranging
from 2 to 20 mL/min/yr, with a mean approximating 12 mL/min/yr
and is similar in both types of diabetes.

112. Factors Contributing To Progression Of
DN

113. Systemic Hypertension
Systemic hypertension is transmitted to the single glomerulus,
which results in increases in glomerular hydrostatic pressure
lead to hyperperfusion and increased capillary pressure –
Glomerular hypertension.
Impaired or abolished renal autoregulation of GFR and renal
plasma flow as demonstrated in type 1 and type 2 diabetic
patients with nephropathy increases vulnerability to
hypertension or ischemic injury of glomerular capillaries.

114. External Complications In Diabetic
Nephropathy
Diabetic retinopathy
• More than 90% of patients with type 1 diabeties and nephropathy
have diabetic retinopathy
• so the absence of retinopathy in type 1 patients with proteinuria
should promote consideration of a diagnosis other than
diabetic nephropathy
• only 60% of patients with type 2 diabetes with nephropathy have
diabetic retinopathy.
Macroangiopathies (e.g., stroke, carotid artery stenosis, coronary
heart disease, and peripheral vascular disease) are two to five
times more common in patients with diabetic nephropathy

115. Diagnosis
Renal biopsy is the gold standard
A renal biopsy may be deferred with the assumed diagnosis of
diabetic nephropathy in the context of
1. Macro albuminuria (>300 mg/24 hours) that has developed
progressively,
2. Microalbuminuria (30-300 mg/24 h) with retinopathy,
3. Microalbuminuria in patients with diabetes for more than 10 years
.

116. AMYLOIDOSIS
Amyloidosis is a condition associated with a number of disorders in
which extracellular deposits of fibrillar proteins are responsible for
tissue damage and functional compromise. These abnormal fibrils are
produced by the aggregation of improperly folded proteins.

117. In Kidney
Amyloidosis of the kidney is the most common and potentially the most serious
form of organ involvement.
Grossly, the kidneys may be of normal size and color, or in advanced cases they
may be shrunken because of ischemia caused by vascular narrowing induced by
the deposition of amyloid within arterial and arteriolar walls.
Histologically, the amyloid is deposited primarily in the glomeruli, but the
interstitial peritubular tissue, arteries, and arterioles are also affected.
The glomerular deposits first appear as subtle thickenings of the mesangial
matrix, accompanied usually by uneven widening of the basement membranes of
the glomerular capillaries.
In time, deposits in the mesangium and along the basement membranes cause
capillary narrowing and distortion of the glomerular vascular tuft. With
progression of the glomerular amyloidosis, the capillary lumens are obliterated
and the obsolescent glomerulus is replaced by confluent masses or interlacing
broad ribbons of amyloid.

119. POLYARTERITIS NODOSA
Polyarteritis nodosa (PAN) is a systemic necrotising vasculitis that
typically affects medium-sized muscular arteries, with occasional
involvement of small muscular arteries.
Renal involvement generally appears with hypertension, haematuria
or proteinuria, and would frequently result in variable degrees of
renal failure, hypertension and perirenal haematomas due to rupture
of renal artery aneurysms.

121. WEGENER’S GRANULOMATOSIS
Granulomatosis with polyangiitis is an uncommon disorder that
causes inflammation of the blood vessels in your nose, sinuses,
throat, lungs and kidneys.
Formerly called Wegener's granulomatosis, this condition is one of a
group of blood vessel disorders called vasculitis. It slows blood flow
to some of your organs.
The affected tissues can develop areas of inflammation called
granulomas, which can affect how these organs work.

123. GOOD PASTEUR SYNDROME
Goodpasture syndrome is an uncommon autoimmune disease in
which lung and kidney injury are caused by circulating autoantibodies
against certain domains of type IV collagen that are intrinsic to the
basement membranes of renal glomeruli and pulmonary alveoli.
The antibodies trigger destruction and inflammation of the basement
membranes in renal glomeruli, giving rise to rapidly progressive
glomerulonephritis.

125. HENOCH-SCHONLEIN PURPURA
IgA vasculitis (formerly known as Henoch Schönlein purpura) is a form of
blood vessel swelling, also known as vasculitis.
It affects the small vessels called capillaries in the skin and the kidneys.
The swelling is due to an abnormal response of the immune system. This
is due to the immune system product called IgA immunoglobulin.
In the kidney, IgA vasculitis (Henoch Schönlein purpura) is characterized
by IgA deposits in a part of the glomerulus where blood is filtered. These
deposits can be seen under a microscope. The pathologist uses a special
staining called immunofluorescence. The deposits will give a fluorescent
glow under the microscope. In most cases, this shows up as protein or
blood in the urine, which you may not even know is there unless you have
a urine test done. Usually this goes away once the illness passes, but
some people develop persistent kidney disease.

127. HEREDITARY NEPHRITIS
Hereditary nephritis refers to a group of hereditary familial renal
diseases associated primarily with glomerular injury.These includes
the following:
1. Alport’s syndrome
2.Fabry’s disease
3.Nail-patella syndrome

128. ALPORT’S SYNDROME
It is nephritic disorder characterized by involvement of kidney,
eye, and ear.
It is most common x linked dominant disease.
 Commonly affect male specially in the age group of 5-20 age.
The disease is due to mutation in type IV collagen.
 Haematuria, lens dislocation,basket wall appearance under
electron microscope.
SNHL:Sensory neural hearing loss

129. Histopathology
•There is segmental glomerular proliferation or sclerosis, or both, and an
increase in mesangial matrix.
•In some kidneys,glomerular or tubular epithelial cells take on a foamy
appearance owing to occumulation of neutral fat and
mucopolysaccharides(foam cells).
•With progression, there is increasing glomerulosclerosis, vascular narrowing,
tubular atrophy, and Interstitial fibrosis.
•With the electron microscope, the basement membrane of glomeruli and
tubules shows irregular foci of thickening or attenuation, with pronounced
splitting and lamination of the lamina densa
•The basement membrane defect has been traced In patients with X-linked
disease to mutations In the gene encoding the a-5 chain of collagen type IV,
interfering with the structure and permeability of the GBM.
•Additional mutations in a newly discovered a-6 chaln occur in some
patients.

131. FABRY’S DISEASE
Another hereditary nephritis is characterized by
accumulation of neutral glycosphingolipids in
lysosomes of glomerular , tubular, vascular and
interstitial cells.

132. Skin Conditions
A common skin condition associated with Fabry disease is a red, non-
painful rash known as angiokeratoma. It usually appears in the area
between the belly and the knees, but may also appear on other parts
of the body such as the lips, tongue, hands, and toes. Additionally, it
may be confined to a small area of the body, or may affect a larger
area.

133. Heart
The heart abnormalities often described with Fabry disease include
changes in the size of the heart (left ventricular enlargement), irregular
heartbeat, and leaky heart valves. Such problems increase the risk of
further heart complications.
Eyes
The surface layer of the eye (cornea) may appear abnormal
when examined by an eye specialist (ophthalmologist).
This unique appearance of the cornea is called cornea
verticillata and while it does not affect vision, it may
become more obvious with time. Cornea verticillata
occurs in approximately three-quarters of patients
with Fabry disease and may be a reliable indicator of
the condition.

134. Ears
Most patients with Fabry disease will have some degree of hearing
loss at some point which can either come on suddenly or develop
over a period of time. Some individuals experience a ringing in the
ears that is called tinnitus.
K i d n e y
Many individuals with Fabry disease experience kidney problems,
commonly beginning in adults in their mid-30s. Abnormally
functioning cells in the kidney weaken the kidneys' ability to filter
waste from the blood to create urine. When the kidneys cannot
properly filter waste, excess protein begins to appear in the urine-a
condition know as proteinuria. Over time, kidney damage may
progress to the point that the kidneys lose some or all ability to
function,requiring dialysis or transplant.

135. NAIL-PATELLA SYNDROME
Nail-patella syndrome osteonychodysplasia is a rare hereditary disease
having abnormality in a-1 chain of collagen V on chromosome 9 associated
with multiple osseous defects of elbows, knees and nail dysplasia. About
half the cases develop nephropathy.
The causes of NPS
 Codes for a protein that is important in organizing embryonic limb
development.
 Located on the long arm of chromosome 9.
Nail
Found in 80% of NPS patients.
 One or more fingers but rarely all.
Affects mostly thumb and Index finger nails.
 May be small and concave with pitty, ridges. splits and /or discoloration.

136. Kidney Disease
 Incidence of kidney disease in NPS patient is approximately
30-50%.
 More apparent later in life.
 Should have regular urinalysis to monitor changes in kidney
function.
Knee Cap
 One or both may be missing or poorly developed.
 If present likely to dislocate.
 Beside the knee cap, other support structure such as bone,
ligaments and tendons may be malformed.