Relax your eyes with the nature: It time for Glomerular Diseases

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• Relax your eyes with the nature It time for
  Glomerular Diseases

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• This lecture will deal with the Glomerular
  DiseasesThese diseases poses Important Medical
  problems.
• Lecture by
• Dr. Amitabha Basu MD

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The Glomerular DiseasesWe will learn it in
following order

• Normal Glomeruli (LM and EM)
• Diagnosis of glomerular disease
• Etiology and pathogenesis of various glomerular
  diseases

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The Normal Glomerulus light microscopy)

• It consists of a tuft of anastomosing
  capillaries.
• Mesangium mesengial cells.

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Electron microscopy
RBC
Foot processes
Basement membrane
Mesangial cells
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Terminologies to understand glomerular diseases

• Glomerulonephritis
• Diffuse
• Focal
• Segmental
• Membranous
• Proliferative
• Sclerosis

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The Diseased GlomerulusTerminology

• The preferred terminology to define diseases of
  the glomerulus is glomerulitis.
• If secondary changes are induced in adjacent
  tubules, one may use the term glomerulonephritis.
  

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Diffuse

• When all glomeruli of the kidney is involved in
  disease process.

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Focal

• When some glomeruli of the kidney is involved in
  disease process.

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Segmental

• When part of a glomerulous is involved in disease
  process.

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Proliferative

• Where there are increased number of cells in
  glomerulimay die to infiltration of PMNs.
• Will result in loss of bowman space and less
  GFR/urine output- commonly result in acute renal
  failure.

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MEMBRANOUS GLOMERULONEPHRITIS (thickened
basement mem.)
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Sclerosis (Trichrome stain)

• Increased collagen, blue colored in this stain.

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Duration

• Acute
• eg Acute Diffuse Proliferative
  glomerulonephritis.
• Chronic
• eg. Chronic Glomerulonephritis

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D. Sclerosis (Trichrome stain)

• Increased collagen, blue colored in this stain.

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Glomerular disease

• Types
• Primary
• Secondary ( due to other systemic disease)
• Hereditary
• Clinical syndromes
• Pathophysiology
• Pathogenesis
• Discussion of individual disease

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Diagnosis of glomerular disease

• Disease of the glomeruli can be
• identified by three syndromes
• Nephrotic syndrome
• Acute Nephritic syndrome
• Recurrent hematuria ( red or smoky urine).

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The Nephrotic Syndrome

• Massive Proteinuria (3.5 g or more/day/1.73 m2)
• 4 protein in urine ( usually frothy)
• Hypoalbuminemia ( plasma proteinlt 3g/dL)
• Generalized Edema (Anasarca)
• Hyperlipidemia and Lipiduria

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Pathophysiology of Nephrotic Syndrome

• Damaged Capillary or Epithelium
• ?
• increased capillary permeability
• ?
• loss of albumin Protenuria
• ?
• Hypoalbuminemia
• ?
• Decreased osmotic Pressure
• ?
• Transudation in the interstitial spaces,
  peritoneum, pleural cavity etc pitting edema

Protenuria produce foamy white foam after
urination.
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Hyperlipidimia and Lipiduria

• Decreased albumin in Blood triggers lipoprotein
  synthesis.
• ?
• Cause high cholesterol
• ?
• Part of which passes through urine.
• ?
• Lipid in the urine is seen as oval fat Body.
• ?
• Some lipid is accumulated in the tubular
  epithelial cells as hyaline droplet.

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The Nephrotic SyndromeComplications

1. Infections Patients are unusually susceptible to
   some infections due to protein loss.
2. Increased Cholesterol Arthrosclerosis.
3. Blood clotting - which may cause venous
   thrombosis ( due to increase viscosity of blood).

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Acute Nephritic syndrome

• Anuria or oliguria.
• Onset weeks-months
• Moderate protenuria (lt 3.5 gm/day) 2, 3.
• Hematuria
• Azotemia
• Hypertension
• Rapidly progressive Glomerulonephritis
• Similar features but onset is quicker (weeks to
  months )? ARF.

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Parthenogenesis of glomerulonephritis

• Three mechanisms
• Deposition of soluble antigen-antibody
• Complex in glomeruli.
• Antibody reacting to in-situ antigen in the
  Glomeruli (Glomerular Basement Membrane antigen).
• Cell mediated immune Nephritis.

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Circulating immune complex nephritis Type III
hypersensitivity reaction

• Diseases this is seen are
• SLE
• Streptococcal
• Hepatitis B
• Treponema pallidum
• Malaria

So IF will show granular deposit
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Antibody reacting to in-situ antigen in the
Glomeruli

• Antibodies (anti GBM antibody) are directed to
  the fixed antigen in the GBM.
• Examples
• Good pasture syndrome
• Heymann nephritis( experimental)

So IF will show smooth linear deposit
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Two Patterns of Deposit (IF)
Granular Circulating immune complex
Linear, smooth In situ disease
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Individual Diseases

1. Minimal change disease
2. Membranous glomerulonephritis
3. Acute glomerulonephritis
4. Crescentic glomerulonephritis
5. Berger's disease (IgA nephropathy)
6. Membrenoproloferative GN
7. Alport syndrome

All are primary glomerular diseases
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Important !!!

• For all Glomerular disease
• Study
• Light microscopic features (LM)
• Electron microscopic features (EM)
• Immunofuroscence feature ( this detect immune
  deposit) IF
• Syndromes

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Minimal change disease ( lipoid nephrosis)

• Syndrome Nephrotic syndrome
• Type of protenuria selective (only albumin comes
  out).
• Due to loss of the normal charge barrier of GBM
• Pathogenesis Lymphokine production by T cells
• Most common cause of nephrotic syndrome in
  children ( 2-6 years).
• Light Microscopy
• Normal glomeruli.
• Lipid droplet in proximal tubular epithelium

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Minimal change disease ( lipoid nephrosis)

• IF no deposit
• EM
• Effacement of epithelial ( podocytes) foot
  process.
• Treatment excellent result with corticosteroid
  stops protenuria quickly.
• Majority recover completely.

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RBC
Effacement of foot processes due to loss of foot
process (giving the appearance of fusion of
the epithelial cell)
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Lipoid Nephrosis( Minimal Change Disease)Urine
Analysis and laboratory

• Urine
• Color Yellow
• Appearance Slightly Cloudy
• Protein 4 ( massive)
• Oval fat body
• All others are negative
• Laboratory
• Serum Cholesterol High
• Complement normal

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Membranous nephropathy (GN)

• Syndrome Nephrotic syndrome
• Most common nephrotic syndrome in ADULT.
• Etiology
• Idiopathic or genetic
• Drug ( penicillamine), renal transplantation,
  Heymann nephritis.
• SLE, Diabetes mellitus
• Adenocarcinoma of lung and colon.

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Morphology

• LM
• HE stain diffuse thickening of the capillary
  wall.
• Silver stain spikes
• IF granular deposit of IgG and C3.
• EM Sub epithelial deposit along Basement
  membrane.

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m

• Membranous GN

HE stain diffuse thickening of the capillary
wall.
Silver stain spikes
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Granular deposit of IgG and C3
Sub epithelial deposit
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Characteristic urinalysis findings and laboratory

• Urine
• Protein 4
• WBC/hpf lt2/hpf
• Laboratory
• low complements

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Membranous GNClinical Features and Prognosis

• Some patient develop hypertension and hematuria.
• It has a variable and indolent course.
• 40 patient progress to renal failure or end
  stage renal disease after 2-20 years.
• 10-30 with partial or complete remission of
  proteinuria.
• No or infrequent effect with steroid.

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Acute Glomerulonephritis
Acute Post-streptococcal Glomerulonephritis
Non-streptococcal causes
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Acute Post-streptococcal glomerulonephritis

• AKA proliferative GN , Post infectious GN
• Syndrome Acute nephritic syndrome
• ASO titer very high.
• Age 2-4 years.
• Etiology
• beta hemolytic group A streptococci infection of
  throat and skin (type 12,4,1)..
• This organism has M protein on cells wall.

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Other Acute Glomerulonephritis

• Non-streptococcal causes
• Pneomococcal pneumonia
• Hepatitis B, C
• SLE, PAN
• Malaria.
• Morphological features of these disease are
  similar to that of acute post streptococcal GN,
  only prognosis would be different.

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Morphology of Acute Post-streptococcal
Glomerulonephritis

• LM
• Hyper cellular, large glomeruli contain
  Neutrophils.
• Tubules RBC cast
• IF granular deposit of IgG, IgM, C3 in all
  glomerulous.
• EM sub epithelial humps.

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Sub epithelial humps
Hyper cellular glomeruli
ASO titer elevate- in poststreptococcal
case. Urine Smoky (due to hematuria),
Dysmorphic RBC. Serum complement level- Low
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Clinical Course

• Past History Throat or skin (impetigo )
  infection.
• Abrupt onset, Malaise, slight fever, nausea.
• Self recovery in child gt95 case.
• Adult
• may progress to crescentic GN.
• May progress to chronic Glomerulonephritis.

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Crescentic Glomerulonephritis (CrGN)

• Aka
• Rapidly Progressive Glomerulonephritis ( RPGN)
  because it quickly (months/weeks) develops
  acute renal failure.
• Syndrome Acute nephritic syndrome.
• Three types
• LM of all types show glomerular crescent.

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Three types
Crescent
Crescent is formed by proliferation of epithelial
cells and monocytes and fibrin.
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Type I CrGN

1. AKA Anti-GBM DISEASE
2. AKA Good pasture syndrome.
3. Presence of Anti GBM antibody in serum this
   react with alveolar capillary ? pulmonary
   alveolar hemorrhage.
4. Present as hematuria and hematemesis.
5. IF Linear and smooth deposit of IgG, and C3 on
   GBM.

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Type II (CrGN)

• Etiology mainly SLE
• IF Granular deposit
• Clinical progress to renal failure.
• Serum ANA present

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Type III (CrGN)

• Aka Pauci-immune ( no immune reaction)
• Diseases
• Wagner Granulomatosis, polyarteritis Nodosa
• Serum
• Normal complements
• Positive ANCA (c or p)
• LM glomerular crescent
• IF and EM no deposit

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Crescentic Glomerulonephritis

• C/F and Prognosis
• Present with the features of Nephritic Syndrome
  (RPGN) ? acute renal failure.
• Prognosis depends upon the number of Crescent in
  kidney so biopsy is indicated.

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• Any Question ?

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• Berger's disease
• Or,
• IgA nephropathy

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GI disease
Lung infection
IgA elevation
Deposit in Kidney
Deposit in dermis
Deposit in blood vessels
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Berger's disease (IgA nephropathy) Please
correct your PPT

• Age Children and Young adult
• Syndrome recurrent hematuria
• This hematuria occur 1-2 days after upper
  respiratory tract infection.
• May progress to Chronic renal Failure(25-50).
• IgA deposit in skin
• Gluten enteropathy.
• LM focal proliferation of mesangial cells
• IF IgA is deposited mainly in mesangium.

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Variant of Berger's disease (IgA nephropathy)

• Disease name Henoch-Schönlein Purpura
• It is associated with
• 1.Skin purpuric Rash
• 2.Abdominal Pain
• 3.Arthritis
• 4.And Kidney change
• Q What is the similarity?
• A Both are caused by IgA deposition in Mesangium
  and skin deposit of IgA.

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Berger's disease and Henoch-Schönlein Purpura
Focal proliferation of mesangial cells
IgA deposit is in mesengium
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• Membranoproliferative Glomerulonephritis
• (MPGN)

Are divided into types I and II.
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Membranoproliferative glomerulonephritis (MPGN I)

• Syndrome Nephrotic syndrome
• Etiology Hepatitis B and C, HIV, SLE, chronic
  liver diseases, chronic Bacterial Infection.
• LM
• HE hyper cellular glumeruli ( but no PMNs) and
  thick GBM.
• Silver stain Tram track
• IF Granular deposit.
• Serum low complements ( particularly C3)

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Tram-tracking Double basement membranes, Why?
Basement membrane splitting
HE Glomerular cellularity and thickening in
the basement membrane
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MPGM type II

• Syndrome Hematuria / chronic renal failure
• 40 progress to end stage renal failure
• IF Dense deposit in GBM .
• Aka dense deposit diseases.
• Serum C3NeF (C3 Nephritic Factor) autoantibody
  is Present.

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Dense deposit
EM note the deposit
These bright deposits are of C3 in capillary
walls and in the mesangium.
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• Focal segmental Glomerulosclerosis (FSGS).

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Focal segmental Glomerulosclerosis (FSGS).

• Age child and adult
• Syndrome Nephrotic syndrome.
• Develop non-selective proteinuria
• Morphology
• HE Sclerosis of some glomeruli, with partial
  involvement.
• Trichrome Blue

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Focal, segmental Glomerulosclerosis
Trichrome stain demonstrates blue, collagen
deposition.
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FSGS

• Etiology
• HIV infection, Heroin addiction
• Inherited congenital disease
• start as a Primary disease
• Clinical
• Poor response to corticosteroid
• Hematuria, Hypertension
• Progression to chronic renal failure
• 50 develop End stage Renal failure
• within 10 years.

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SECONDARY GLOMERULONEPHRITIS (SYSTEMIC) more
common

1. Diabetes Mellitus
2. Systemic Lupus Erythematosus.
3. Amyloidosis
4. Goodpasture Syndrome
5. Wagner granulomatosis
6. Henoch-Schönlein Purpura
7. Bacterial Endocarditis

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Glomerular disease with-

• Systemic lupus erythematosus Nephrotic syndrome
• Diabetes mellitus Nephrotic syndrome
• Amyloidosis Nephrotic syndrome

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Glomerular changes in SLE positive dsDNA

1. Crescentic GN RPGN
2. Focal proliferative GN 25 case ANS
3. Membranous GN (Wire loop thickening) NS
4. Mesangial lupus GN NS
5. Normal glomerulous ( rare) NS

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SLE LM wire loop IF C1q deposit
Serum complement low ( typically C1q)
C1q deposit EVERYWHERE
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Diabetic kidney
Nodular hyaline deposit- PAS positive
Hyaline arteriolosclerosis
Kimmelstiel-Wilson disease or Nodular
glomerulosclerosis
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Amyloidosis of Kidney

• Gross waxy pale surface
• LM
• Pink hyaline like deposit
• in mesangium
• Cogored
• LM brick red
• Polarized light apple green birefrenges
• Type of amyloid
• Primary Amyloid light chain ( Multiple myeloma)
• Secondary (reactive) AA

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• We will now start Alport syndrome (hereditary)

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Alport syndrome

• Syndrome recurrent hematuria
• Family history of Chronic renal failure
• Sex Male child gt Female child
• Early onset of renal failure
• Nerve deafness
• Cataract, lens dislocation, corneal dystrophy.
• Inheritance X- Linked autosomal Recessive or
  Dominant.

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Alport syndrome

• Defective gene (alfa5) produce abnormal Collagen
  Type IV.
• LM irregular thickening of glomeruli
• LM foamy cells in tubules

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Key words of clinical features disease
Acute Nephritic syndrome Nephrotic syndrome
Acute Glomerulonephritis Post streptococcal Non post streptococcal Minimal change disease Membranous GN, MPGN 1
Acute Glomerulonephritis Post streptococcal Non post streptococcal Focal segmental glomerulosclerosis (FSGS).
Acute Glomerulonephritis Post streptococcal Non post streptococcal Systemic diseases diabetes, SLE, Amyloidosis.
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Key words of clinical features disease
Recurrent Hematuria Rapidly progressive Glomerulonephritis
IgA nephropathy ( Berger's disease) Henoch-Schönlein Purpura Cresentic GN Good pasture syndrome Wegner Granulomatosis Polyarteritis nodosa SLE
Alport syndrome ( family history of hematuria) Cresentic GN Good pasture syndrome Wegner Granulomatosis Polyarteritis nodosa SLE
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• Chronic Glomerulonephritis.

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Clinical Increasing BUN and creatinine,
uremia Hypertension
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Chronic glomerulonephritis

• 30 -50 of all patient needs hemodialysis and
  Renal Transplantation.
• Gross cortical atrophy
• LM Non specific ( biopsy not useful)
• Scarring of Glomeruli, bowmens space
• Hyalinization of glomeruli.
• Interstitial fibrosis.
• Tubular atrophy
• Thickening of the small and medium sized arteries.

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Symmetrically Contracted SMALL Kidneycoarse
Granular Surface
Note the hyalinized glomeruli Some are still
viable!
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Remember !!

• Chronic glomerulonephritis ? End stage kidney.
• End stage kidney (renal) disease GFR is lt 5 of
  the normal.
• All glomeruli sclerosed.
• Patient cannot live without transplantation or
  regular dialysis.

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End stage kidney no normal glomeruli !!!!
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Progression of glomerular disease
Complete recovery
ARF
Chronic GN Coarsely granular Kidney
Death
Chronic Renal failure/ Ure8484mia
Any other kidney diseases
ESRD- all glomeruli sclerosed
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Diagnosis of glomerular disease
24 hour urine
Rapid ?BUN/ Creatinine and rapid oliguria/
hematuria
2, 3
4
RPGN
Nephrotic syndrome
Nephritic syndrome
Hematuria
Child
Child
Adult
Adult
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End of the Primary Diseases of Kidney

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