glomerular disease

RENAL SYSTEM

The kidneys:An Excretory organ or a Regulatory organ?!!!

The main purpose of the kidney is to separate urea, mineral salts, toxins, and other waste products from the blood.

They also do the job of conserving water, salts, and electrolytes.

At least one kidney must function properly for life to be maintained.

The Kidneys- function

The Kidney Diagram

The Kidney Nephron Diagram

GLOMERULUS:

Glomerular capillary wall:1. Fenestrated endothelium –70 – 100 nm,2. Glomerular Basement Membrane

.. Lamina rara interna,

.. Lamina densa,

.. Lamina rara externa3. Visceral epithelial cells (podocytes)4. Mesangial cells – contract, proliferate, collagen & matrix, secretion;

THE KIDNEY

Three-dimensional schematic drawing of the glomerulus

Afferent arteriole

Efferent arteriole

Bowman’s Capsule

Basement membrane

Visceral Epithelium(Podocyte)

Parietal Epithelium

Capillary loops

Bowman’s Space

Endothelial cells

Stucture of renal

glomerulus

Mesangial matrix and cell

Ultramicroscopic Stucture of glomerullar Capillaries

Filtration Mem

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Light microphotograph of glomerulus

•Normal celluarity

;•Patent capillary lumens

RENAL PATHOLOGY

DISEASES OF GLOMERULI

DISEASES OF TUBULES

DISEASES OF INTERSTITIUM

DISEASES OF BLOOD VESSELS

DISEASES OF THE KIDNEY

AZOTEMIA – BUN, Creatinine --- GFR

UREMIA – Azotemia + Clinical signs and

symptoms + Biochemical abnormalities

+ Involvement of G I tract, Peripheral

nerves

.. and heart;

Clinical manifestations of renal diseases

Glomerular disease

DEFINITION Abnormalites of glomerular funtion can be

caused by damage to the major components of the glomerulus: Epithelium (podocytes), Basement membrane, capillary endothelium, mesangium.

Damage manifested by an inflammatory process.

GLOMERULAR DISEASES

Clinical manifestation of glomerular injury

Histologic alterations

a) hypercellularity: i) cell proliferation of mesangial cells or

endothelial cellsii) leukocyte infiltration (neutrophils,

monocytes and sometimes lymphocytes)iii) formation of crescents

- epithelial cell proliferation (from immune/inflammatory injury)- fibrin thought to elicit this injury (TNF, IL-1, IFN- are others)


b) basement membrane thickening - thickening of capillary wall

c) hyalinization (hyalinosis) and sclerosis

-accumulation of material that is

eosinophilic and homogeneous

- obliterates capillary lumen of

glomerulus (sclerotic feature)


classification is based on histology. Subdivided:

a) diffuse (all glomeruli)b) global (entire glomerulus)c) focal (portion of glomeruli)d) segmental (part of each glomerulus)e) mesangial (affecting mesangial

region)


What causesglomerular disease ?

Most are of immunologic origin, and

caused by immune complexes !

• metabolic stress: DN• mechanical stress:• hypertension

Antibody mediated injury In situ immune complex deposition Fixed intrinsic tissue antigens collagen type4 antigen [anti GBM-nephritis] Heymann antigen [membranous nephropaty Mesangial antigens Circulating immune complex deposition Endogenous antigen[DNA,Nuclear

proteins,immunoglobulins,igA] Exogenous antigen [infectiousagents,drugs]Cytotoxic antibodiesCell mediated immune injuryActivation of alternative complement

pathway

Pathogenesis of glomerular injury

Pathogenesis of Glomerular Disease

Immune mechanisms underlie most cases of primary GN and many of the secondary cases

a) 2 forms of Ab-associated injuryi) injury resulting from soluble Ag-

Ab deposits in glomerulusii) injury from Ab reacting in-situ

with glomerulus


• In Situ Immune Complex Depositiona) Ab act directly with intrinsic tissue

Ag “planted” in the glomerulus from

the circulationb) 2 forms of Ab-mediated glomerular injury

i) anti-GBM Ab-induced nephritis- Ab directed against fixed Ag

in ii) Heymann nephritis- a form of membranous GN- Ab bind along GBM in

“granular pattern”


Antibody mediated GN - Circulating Immune complex

Location: Mesangial and sub-endothelial

Antibody mediated GN -

In-situ Immune complex

Location: GBM sub-epithelial

• circulating auto antibodies with intrinsic autoantigens (component of normal parenchyma)

Antibody mediated GN - In-situ Immune complex (trapped Ag)

Location: GBM sub-epithelial

Extrinsic antigens planted within the glomerulus

Pathogenesis

In situ immune complex

Circulating immune complex

Activation of T lymphocytes

Acitvation of complements

cytokines

C5b-9 C5a,C3a

Epithelial, mesangial,Endothelial cells

Macrophagepolynuclear leucocyte, platelets

Mesangial cells

oxidative stress, protease, matrix accumulations

Glomerular Disease

Glomerular DiseasesPRIMARY GLOMERULOPATHIES Acute proliferative glomerulonephritis Post-infectious Rapidly progressive (crescentic) glomerulonephritis Membranous glomerulopathy Minimal-change disease Focal segmental glomerulosclerosis Membranoproliferative glomerulonephritis IgA nephropathy Chronic glomerulonephritis SYSTEMIC DISEASES WITH GLOMERULAR INVOLVEMENT Systemic lupus erythematosus Diabetes mellitus Amyloidosis Goodpasture syndrome Microscopic polyarteritis/polyangiitis Wegener granulomatosis Henoch-Schönlein purpura Bacterial endocarditis HEREDITARY DISORDERS Alport syndrome Thin basement membrane disease Fabry disease

TABLE 20-2 -- Glomerular DiseasesPRIMARY GLOMERULOPATHIES Acute proliferative glomerulonephritis Post-infectious Other Rapidly progressive (crescentic) glomerulonephritis Membranous glomerulopathy Minimal-change disease Focal segmental glomerulosclerosis Membranoproliferative glomerulonephritis IgA nephropathy Chronic glomerulonephritis SYSTEMIC DISEASES WITH GLOMERULAR INVOLVEMENT Systemic lupus erythematosus Diabetes mellitus Amyloidosis Goodpasture syndrome Microscopic polyarteritis/polyangiitis Wegener granulomatosis Henoch-Schönlein purpura Bacterial endocarditis HEREDITARY DISORDERS Alport syndrome Thin basement membrane disease Fabry disease




Various types of glomerulopathies are characterized by one or more of four basic tissue reactions:

1. Hypercellularity

2. Basement membrane thickening

3. Hyalinosis

4. Sclerosis

HISTOLOGIC ALTERATIONS

ACUTE PROLIFERATIVE (Poststreptococcal,

Postinfectious)GLOMERULONEPHRITIS

Common form of GN in developing countries. 6 to 10yrs of age 1 - 4 weeks after a streptococcal infection of pharynx

or skin (Impetigo) Group A β-haemolytic streptococci - types 12, 4, 1 Immunologically mediated disease Immune Complex mediated Anti - endostreptosin & other cationic antigens . Serum – C

Poststreptococcal Glomerulonephritis

Glomeruli- Enlarged , hypercellular glomeruli - infiltration by leukocytes - proliferation of endothelial &

mesangial cells, - crescent formation (severe cases)

- obliteration of capillary lumen

Fibrin deposition in capillary lumen &

mesangium.

Interstitial edema and leucocytic infiltration

Tubules contain red cell cast.

Microscopy

Diffuse

Normal glomerulus

Acute Proliferative GN

AcuteProliferative GN

Immunofluorescence:

- granular deposits of IgG , IgM , C3 in

mesangium , along BM

Electron microscopy: Discrete , amorphous , electron dense

deposits on epithelial side of BM often having the appearance of “humps

Sudden onset in a young child - malaise, fever , nausea , oliguria , hematuria,

Edema , mild - moderate hypertension , elevation of BUN

Urine - RBC casts, proteinuria Lab - antistreptococcal antibody titre , C3

Clinical Course

95% -- children recover,< 1% - rapidly progressive GN1-2% - slow progression to chronic GN,

Persistent proteinuria, Abnormal GFRAdults

Prognosis

Poorprognosis

CRESCENTIC GLOMERULONEPHRITIS

CRESCENTIC GLOMERULONEPHRITIS

(Rapidly Progressive Glomerulonephritis)[RPGN]

Severe glomerular injury Does not denote a specific etiologic form of

GN Clinically - rapid & progressive loss of renal

function & death within weeks to months Crescents in most glomeruli – parietal

epithelial cells proliferation;

RPGN(Crescentic Glomerulonephritis)

Type - I RPGN ( Anti-GBM antibody induced disease)

.. Idiopathic,

.. Goodpasture syndrome; Type - II RPGN (immune Complex)

.. Idiopathic, postinfecious, SLE, Henoch-Schonlein purpura (IgA), others;

Type - III RPGN ( Pauci-immune ) .. ANCA associated, Idiopathic,

Wagener granulomatosis, PAN;

Classification & Pathogenesis

Linear deposits of IgG , C3 in GBM Cross reaction with pulmonary alveolar BM

Good - Pasture’s antigen located in

noncollagenous portion of α3

domain of collagen type - IV

Type I - RPGN ( Crescentic GN )

Immune complex mediated disease

Complication of immune complex

nephritides - Post infectious GN , SLE ,

IgA nephropathy

Granular deposit of immune complexess of

IgG and C3 along glomerular capillary walls.

IF - lumpy bumpy granular pattern

Type - II RPGN

Lack of anti GBM antibody , immune complexes by IF , EM

ANCA present- defect in humoral immunity. Usually a component of systemic vasculitis

- Wegeners Granulomatosis , Polyarteritis Idiopathic

Type III RPGN( Pauci - immune )

Gross : Kidneys enlarged , pale ,smooth outer surface.

C/S petechial hemorrhages on cortical surface

Morphology

Crescentsproliferation of parietal cells migration of monocytes ,macrophages into Bowmans space Crescents obliterate Bowman’s space ,

compress glomerular tuft Fibrin strands are prominent between cellular

layers in the cresents.

Microscopy

Crescents Sclerosis EM : subepithelial deposits ruptures in GBM IF : Postinfectious cases - granular Good Pastures syndrome - linear

Idiopathic - granular / linear

Microscopy of RPGN (cont. )

Electron micrograph showing characteristic wrinkling of GBM with focal disruptions (arrows).

Hematuria , RBC casts , proteinuria Hypertension , Edema Good - Pastures syndrome -

Hemoptysis Anti - GBM , antinuclear , ANCA Renal involvement - progressive

Clinical Course

a) massive proteinuria (> 3.5 g/day) b) hypoalbuminemia c) generalized edema d) hyperlipidemia and lipiduria

Nephrotic Syndrome

Clinical syndromes and presentation

Latent GN(asymptomatic

urinary abnormalities)

Nephrotic syndrome

Acute GN RPGN Chronic GN

microscopic or Macroscopic hematuriaProteinuria

Dysmorphic Glomerular erythrocytes

Proteinuria>3.5g/dHypoalbuminemiaHyperlipidemiaEdema

HematuriaProteinuria(1-3g/d)ARFEdemaHypertensionRed cell casts

•Rapidly deterioration of renal function•Hematuria, Proteinuria• oliguria or anuriaRed cell casts•With or without systemic symptom

•Hematuria, Proteinuria•Hypertension•Reduced GFR

glomerular disease

Health & Medicine

glomerular capillary

glomerular basement

mesangial cells contract

capillary endothelium

associated injury i

injury tnf

immune complexes

b basement membrane