Relax your eyes with the nature: It time for Glomerular Diseases 1

This lecture will deal with the Glomerular Diseases These diseases poses Important Medical problems.

Lecture by: Dr. Amitabha Basu MD 2

The Glomerular Diseases We will learn it in following order

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

3

The Normal Glomerulus

: light microscopy) • It consists of a tuft of anastomosing capillaries.

• Mesangium: mesengial cells.

4

Electron microscopy

RBC Foot processes Basement membrane Mesangial cells 5

Terminologies to understand glomerular diseases • Glomerulonephritis • Diffuse • Focal • Segmental • Membranous • Proliferative • Sclerosis 6

The Diseased Glomerulus Terminology

•

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.

9

Segmental

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

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Proliferative

• Where there are increased number of cells in glomeruli…may 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:

1. Nephrotic syndrome 2. Acute Nephritic syndrome 3. Recurrent hematuria ( red or smoky urine).

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Nephrotic syndrome Acute nephritic syndrome/ RPGN Recurrent Hematuria Glomerular diseases 18

The Nephrotic Syndrome 1.

2.

3.

4.

•

Massive Proteinuria ( 3.5 g or more/day/1.73 m 2 ) 4+ protein in urine ( usually frothy) Hypoalbuminemia ( plasma protein< 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 Syndrome Complications 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). 22

Acute Nephritic syndrome

Anuria or oliguria.

• Onset: weeks-months –

Moderate protenuria (< 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:

1. Deposition of soluble antigen-antibody Complex in glomeruli.

2. Antibody reacting to in-situ antigen Glomeruli ( G lomerular B asement M embrane antigen).

in the 3. Cell mediated immune Nephritis

.

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Circulating immune complex nephritis: Type III hypersensitivity reaction

• Diseases this is seen are: 1. SLE 2. Streptococcal 3. Hepatitis B 4. Treponema pallidum 5. 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 1. Light microscopic features (LM) 2. Electron microscopic features (EM) 3. Immunofuroscence feature ( this detect immune deposit)= IF 4. Syndromes 29

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 T cells : Lymphokine production by 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: – H&E 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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Membranous GN

m

H&E stain: diffuse thickening of the capillary wall.

Silver stain: spikes

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Sub epithelial deposit Granular deposit of IgG and C3

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Characteristic urinalysis findings and laboratory

•

Urine:

–

Protein 4+

– WBC/hpf = <2/hpf • Laboratory: – low complements 38

Membranous GN Clinical 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 >95% 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: G ood pasture syndrome.

1. Presence of Anti GBM antibody in serum: this react with alveolar capillary → pulmonary alveolar hemorrhage. 2. Present as hematuria and hematemesis.

3. 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 49

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. 51

Any Question ?

52

Berger's disease Or,

IgA nephropathy 53

Lung infection GI disease Deposit in Kidney Deposit in blood vessels IgA elevation Deposit in dermis 54

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:

–

H&E: 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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H&E: Glomerular cellularity and thickening in the basement membrane “Tram-tracking”: Double basement membranes, Why? = Basement membrane splitting

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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. 61

EM: note the deposit Dense 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: – H&E: Sclerosis of some glomeruli, with partial involvement.

– Trichrome: Blue 64

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

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FSGS

A.

B.

Etiology: A. HIV infection, Heroin addiction B. Inherited congenital disease C. start as a Primary disease Clinical: A. Poor response to corticosteroid

B. Hematuria, Hypertension

C. Progression to chronic renal failure D. 50% develop End stage Renal failure within 10 years.

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SECONDARY GLOMERULONEPHRITIS (SYSTEMIC ): more common 1.

2.

3.

4.

5.

6.

7.

Diabetes Mellitus Systemic Lupus Erythematosus.

Amyloidosis Goodpasture Syndrome Wagner granulomatosis Henoch Schönlein Purpura Bacterial Endocarditis 67

Glomerular disease with:-

Systemic lupus erythematosus: Nephrotic syndrome Diabetes mellitus: Nephrotic syndrome Amyloidosis: Nephrotic syndrome 68

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 69

Serum complement low ( typically C1q)

SLE: LM: wire loop IF: C1q deposit

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) 73

Alport syndrome

• Syndrome: recurrent hematuria – Family history of Chronic renal failure – Sex: Male child > 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 75

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 Focal segmental glomerulosclerosis (FSGS).

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 Alport syndrome (+ family history of hematuria) Cresentic GN 1. Good pasture syndrome 2. Wegner Granulomatosis 3. Polyarteritis nodosa 4. SLE 77

Chronic Glomerulonephritis.

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RELATIVE RATES OF CONVERSION ACUTE GN TO CHRONIC GN

2-3% 100% 10% IN 10YRS 40%EVENTUALLY 50% IN 10 YRS 50% IN 10 YRS 50% IN 20 YEARS Clinical: Increasing BUN and creatinine, uremia Hypertension 79

“

Chronic glomerulonephritis“

• 30 -50% of all patient needs hemodialysis and Renal Transplantation.

• Gross: • LM: cortical atrophy Non specific ( biopsy not useful) – – – – –

Scarring of Glomeruli, bowmen’s space Hyalinization of glomeruli.

Interstitial fibrosis.

Tubular atrophy Thickening of the small and medium sized arteries.

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Symmetrically Contracted SMALL Kidney coarse Granular Surface Note the hyalinized glomeruli Some are still viable!

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Remember !!

•

Chronic glomerulonephritis → stage kidney.

End

•

End stage kidney (renal) disease: GFR is < 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 Death

Chronic GN Coarsely granular Kidney

Any other kidney diseases

Chronic Renal failure/ Ure8484mia

ESRD- all glomeruli sclerosed 84

4+ Nephrotic syndrome Child 24 hour urine 2, 3+ Diagnosis of glomerular disease Rapid ↑BUN/ Creatinine and rapid oliguria/ hematuria RPGN Nephritic syndrome Child Hematuria Adult Adult 85

End of the Primary Diseases of Kidney

THANK YOU YOU ARE WELCOME TO ASK ANY QUESTION ANY TIME 86