Glomerular diseasesGlomerular diseases

Lecture from pathological physiology January, 2005Lecture from pathological physiology January, 2005

Anatomy of the glomerulus and the Anatomy of the glomerulus and the juxtaglomerular apparatusjuxtaglomerular apparatus

All three layers (endothelium, glomerular basement membrane, slit pores between podocytes)are negatively charged

Mesangium is contractable

Visceral epithelium (podocytes)

Basement membrane

Endothelium(fenestrated)

Glomerular basement membrane (GBM)

Fig. Glomerular basement membrane (GBM)

Glomerular diseases (glomerulopathy)Glomerular diseases (glomerulopathy)

heterogeneous group of diseasesheterogeneous group of diseases

Dividing: Dividing:

a)a) Primary glomerulopathyPrimary glomerulopathy

b)b) Secondary glomerulopathySecondary glomerulopathy

– – can be manifestation of systemic diseases, vascular, metabolic or can be manifestation of systemic diseases, vascular, metabolic or genetic disorders affecting also other organsgenetic disorders affecting also other organs

The mechanisms for glomerular injury are complexThe mechanisms for glomerular injury are complex

more often are iniciated by anmore often are iniciated by an immune responseimmune response

Immunopathologic mechanismsImmunopathologic mechanisms

Damage of kidney depend on:Damage of kidney depend on:- mechanism and intensity of immune reactionmechanism and intensity of immune reaction

- collocation of antigens (Ag)collocation of antigens (Ag)

Mechanisms:Mechanisms:

Damage by immunocomplexesDamage by immunocomplexes Damage by cytotoxic antibodies (Ab)Damage by cytotoxic antibodies (Ab) Cell-mediated immune injury = delayed-type Cell-mediated immune injury = delayed-type

hypersensitivityhypersensitivity Damage by complement and proinflammatory mediatorsDamage by complement and proinflammatory mediators

Cytotoxic (Type II) reactionCytotoxic (Type II) reaction – antibody mediated cytotoxicity (ADCC) – antibody mediated cytotoxicity (ADCC)

These occur when antibodies interact These occur when antibodies interact with antigens found on cell with antigens found on cell surfacesurface

2 mechanisms of cytotoxicity:2 mechanisms of cytotoxicity:

1.1. Ab mediate cell destruction Ab mediate cell destruction via mechanism ADCC (cell via mechanism ADCC (cell cytotoxicity dependent on Ab)cytotoxicity dependent on Ab)

2.2. Ab directed against cell-Ab directed against cell-surface antigens mediate cell surface antigens mediate cell destruction via complement destruction via complement activationactivation

Type III reaction – immune complex-Type III reaction – immune complex-mediated hypersensitivitymediated hypersensitivity

- The reaction of antibody with The reaction of antibody with antigen generates immune antigen generates immune complexes. In some cases, large complexes. In some cases, large amounts of immune complexes can amounts of immune complexes can lead to tissue damagelead to tissue damage

They deposited in variousThey deposited in various tissuestissues induce induce complement activation complement activation

and ensuing inflammatory response and ensuing inflammatory response

Antigens can be:Antigens can be:a)a) Endogenous – for example DNA in Endogenous – for example DNA in

SLESLEb)b) Exogenous – bacteria, viral, Exogenous – bacteria, viral,

parasitical Agparasitical Ag

The magnitude of the reaction depends on the quantitity of immune The magnitude of the reaction depends on the quantitity of immune complexes as well as distribution within the wall of glomerular capillarycomplexes as well as distribution within the wall of glomerular capillary

Location of immune deposits in the glomerular capillary wallLocation of immune deposits in the glomerular capillary wall

Delayed – type hypersensitivity (Type IV)Delayed – type hypersensitivity (Type IV)

T lymphocytes may also recognize T lymphocytes may also recognize antigenantigen

When they do, a mononuclear cell When they do, a mononuclear cell infiltrate may accumulate at the infiltrate may accumulate at the site of Ag concentration and site of Ag concentration and lead to the elaboration of toxic lead to the elaboration of toxic products and tissue injuryproducts and tissue injury

Four major pathogenetic forms of glomerular Four major pathogenetic forms of glomerular injuryinjury

In non-proliferativeIn non-proliferative glomerulopathy: glomerulopathy:

Damage by Damage by antibodiesantibodies Damage mediate by Damage mediate by complementcomplement

In proliferativeIn proliferative glomerulopathy: glomerulopathy:

Damage by Damage by circulating proinflammatory cellscirculating proinflammatory cells (especially (especially neutrophils and macrophages)neutrophils and macrophages)

Damage by Damage by localy activatinglocaly activating rezident cells rezident cells (for example (for example mesangial mesangial cellscells))

Classification of glomerulopathiesClassification of glomerulopathies

• Clinical:Clinical: primary x secondary primary x secondary

• According According time period:time period: acute x subacute x chronic acute x subacute x chronic

• According According renal biopsyrenal biopsy: focal x segmental x diffuse: focal x segmental x diffuse

• According number of According number of cellscells: non-proliferative x: non-proliferative x proliferativeproliferative

• According According imunofluorescenceimunofluorescence: :

Pathogenic mechanisms of glomerular diseasesPathogenic mechanisms of glomerular diseases

NEPHRITICNEPHRITIC

NEPHROTICNEPHROTIC

Chronic Chronic glomerulonephritisglomerulonephritis

Pathogenesis of nephritic diseasesPathogenesis of nephritic diseases

Histologic patternHistologic pattern

• May not correlate with May not correlate with the clinical presentation the clinical presentation

• Various histological Various histological types of types of glomerulonephritisglomerulonephritis

B: “Minimal changes” GN = lipoid nephrosis: some mesangial proliferation, edematous podocytes, fusion (“loss”) of their foot processes

C: Intracapillary mesangial proliferative GN: proliferation of endothelia and mesangium, peeling off of enthelial cells from the GBM, duplication of GBM, “humps” formed by immunocomplexes

D: Crescentic GN: proliferation of all components (aggressive white cells, endo- and epithelia, mesangium, epitheloid and giant cells), leakage of fibrin. Hypersensitivity reaction type II or IV

E: Membranous GN: Precipitation of immunoglobulins on the outer surface of the GBM (“spikes” complete incorporation of Ig into the membrane)

F: Proliferative sclerotizing GN: advanced mesangial proliferation narrowing and destruction of capillaries

Acute glomerulonephritis (poststreptococcal Acute glomerulonephritis (poststreptococcal GN)GN)

Is commonly caused by infection by certain Is commonly caused by infection by certain strains of group A beta-hemolytic strains of group A beta-hemolytic Streptococci (pharyngitis, pyoderma)Streptococci (pharyngitis, pyoderma)

Ab against streptococci react with vimentin Ab against streptococci react with vimentin

imunokomplexesimunokomplexes

nephritis develop after a nephritis develop after a latent periodlatent period of of about 2-3 weeksabout 2-3 weeks

Clinical syndromeClinical syndrome: nephritic syndrom: nephritic syndrom

Histologic patternHistologic pattern: intracapillary : intracapillary proliferation of mesangial and endothelial proliferation of mesangial and endothelial cells with subepithelial („humps“) and cells with subepithelial („humps“) and subendothelial deposits (C3, or IgG)subendothelial deposits (C3, or IgG)

Acute diffuse proliferative GN

Postinfectional non-streptococcus Postinfectional non-streptococcus glomerulonephritisglomerulonephritis

Acute glomerulonephritis can develope also in the course of Acute glomerulonephritis can develope also in the course of other infections: other infections:

- stafylococci - herpes virus- stafylococci - herpes virus

- pneumococci - EBV- pneumococci - EBV

- Klebsiella pneumonie - virus hepatitis B- Klebsiella pneumonie - virus hepatitis B

GN in infection endocarditisGN in infection endocarditis

GN in visceral abscessus (especially lung)GN in visceral abscessus (especially lung)

Histologic patternHistologic pattern and and clinical syndromeclinical syndrome – similar one as in poststreptococcal GN – similar one as in poststreptococcal GN

Focal proliferative glomerulonephritisFocal proliferative glomerulonephritis

- different etiology:- different etiology:

IgA nefropathyIgA nefropathy Nephritis in systemic lupus erythematodes (SLE)Nephritis in systemic lupus erythematodes (SLE) Nephritis in bacterial endocarditisNephritis in bacterial endocarditis Henoch-SchHenoch-Schöölein purpuralein purpura

Rapidly progressive glomerulonephritis Rapidly progressive glomerulonephritis (RPGN)(RPGN)

Heterogeneous group of diseases, it is characterised by intense Heterogeneous group of diseases, it is characterised by intense proliferation of glomerular/capsular epithelial cells in the form of a proliferation of glomerular/capsular epithelial cells in the form of a crescent.crescent.

crescemtcrescemt = accumulation and proliferation of extracapillary cells = accumulation and proliferation of extracapillary cells..

The glomerular capillaries collapse and are bloodless, and fibrin can be The glomerular capillaries collapse and are bloodless, and fibrin can be identified within the capsuleidentified within the capsule

it can it can stimulastimulatte proliferae proliferation of tion of pariet parietaal epitl epithhelieliaal l cellscells

deposits of fibrin compress the glomerula capillaries tuftdeposits of fibrin compress the glomerula capillaries tuft

(( GFR and destruction of glomerulus) GFR and destruction of glomerulus)

Three forms of RPGNThree forms of RPGN

GN with creation of antiobdiesGN with creation of antiobdies (IgG, IgA) agains (IgG, IgA) agains GBM (anti-GBM)GBM (anti-GBM)

- linear deposits of Ig- linear deposits of Ig

(+ alveolocapillary BM) (+ alveolocapillary BM) Goodpastures´ syndrome Goodpastures´ syndrome

GN with granular deposits of Ig and complemenGN with granular deposits of Ig and complemen - - formation of crescent is complication less serious formation of crescent is complication less serious

intracapillary proliferative GN (IgA nefropathy, SLE, intracapillary proliferative GN (IgA nefropathy, SLE, acute GN e.g.)acute GN e.g.)

GN with ANCA antibodies GN with ANCA antibodies - - ANCA ab (Ab agains cytoplasma of neutrophiles)ANCA ab (Ab agains cytoplasma of neutrophiles) 2 forms – systemic disorders 2 forms – systemic disorders ((Wegener granulomatosis)Wegener granulomatosis) - only renal disease- only renal disease

Crescent GN

Goodpastures´ syndromeGoodpastures´ syndrome

It is charecterised antibodies against basal membrane of glomeruli It is charecterised antibodies against basal membrane of glomeruli (alveolocapillary membrane)(alveolocapillary membrane)

Etiology:Etiology: combination of exogenous factors (smoking, infection, toxines) combination of exogenous factors (smoking, infection, toxines) with genetic predisposition (HLA B7, DR2)with genetic predisposition (HLA B7, DR2) Pathogenesis:Pathogenesis: GBM is composed by collagen IV with proteins GBM is composed by collagen IV with proteins (laminine, entaktine, tenascine) and proteoglycans(laminine, entaktine, tenascine) and proteoglycans

Goodpastures antigenGoodpastures antigen (localised in C-terminal non-collagen globular (localised in C-terminal non-collagen globular domain (NC1) of the molecule domain (NC1) of the molecule 3 chain of collagen IV3 chain of collagen IV formation of Ab (IgG1 – can activate complement)formation of Ab (IgG1 – can activate complement) damage of BMdamage of BM

Clinical manifestation:Clinical manifestation: typically presents with crescentic glomerulonephritis typically presents with crescentic glomerulonephritis + pulmonary hemorrhage+ pulmonary hemorrhage

Slowly progressive glomerulonephritisSlowly progressive glomerulonephritis

Group of GN called Group of GN called membrane-proliferative GNmembrane-proliferative GN 2 forms: 2 forms: in in 1 form 1 form : - : - levels of complements in plasma levels of complements in plasma - subendothelial and mesangial deposits are present- subendothelial and mesangial deposits are present findings: findings: proteinuriaproteinuria or picture of or picture of nephrotic syndromnephrotic syndrom

in in 2 form2 form: - activation of complement is due to nephritic factor C3 : - activation of complement is due to nephritic factor C3 - intramembranous deposits are present- intramembranous deposits are present

findings: findings: proteinuriaproteinuria or picture of or picture of nephritic syndromnephritic syndrom (similary as in (similary as in RPGN)RPGN)

Pathogenesis of nephrotic diseasesPathogenesis of nephrotic diseases

„„Minimal changes“ GN (lipoid nephrosis)Minimal changes“ GN (lipoid nephrosis)

Especially in childrenEspecially in children Pathogenesis ambiguousPathogenesis ambiguous – connection with – connection with

viral infections, vaccination, atopy, viral infections, vaccination, atopy, application some drugs (antiphlogistics etc.), application some drugs (antiphlogistics etc.),

Association with several HLA antigens Association with several HLA antigens (DRw7, B8, B12 …)(DRw7, B8, B12 …)

Finding:Finding: loss of negative charge loss of negative charge (( permeability for some proteins – permeability for some proteins – albumins)albumins)

Histologic pattern:Histologic pattern: fusion („loss“) of foot fusion („loss“) of foot processes of podocytes (pedicules), edematous processes of podocytes (pedicules), edematous podocytes, some mesangial proliferationpodocytes, some mesangial proliferation

TherapyTherapy: corticoids: corticoids

Focal (segmental) glomerulosclerosisFocal (segmental) glomerulosclerosis

More serious degreeMore serious degree

- - focalfocal: : << 50% glomerul 50% glomerulii are affectedare affected

- - difdiffusefuse: : >> 50% glomerulů 50% glomerulů are affectedare affected

- - segmentsegmentaall: : only a part of the glomerular tuft is only a part of the glomerular tuft is involvedinvolved

- - glomerulosglomeruloscclerlerosisosis: oblitera: obliterationtion of capillary of capillary lumenslumens

Membranous GNMembranous GN

• Diffuse thickness of GBMDiffuse thickness of GBM due to due to deposition deposition of IKof IK in basement membrane in basement membrane

• Strong association with HLA (B8, DR3) and Strong association with HLA (B8, DR3) and genes of alternative way of activation of genes of alternative way of activation of complements (Bf)complements (Bf)

• Often secondary etiologyOften secondary etiology:: - drugs (Au, penicilamin…)- drugs (Au, penicilamin…) - tumors (especially ca GIT)- tumors (especially ca GIT) - infection (hepatitis B) - infection (hepatitis B)

• Clinical manifestationClinical manifestation: nephrotic syndrome : nephrotic syndrome with mikroscopic hematuria and sometimes with mikroscopic hematuria and sometimes hypertensionhypertension

• Therapy: according etiologyTherapy: according etiology

Stages of membranous GNStages of membranous GN

Idiopatic membranous glomerulopathy

Membranoproliferative (mesangiocapillary) Membranoproliferative (mesangiocapillary) glomerulopathyglomerulopathy

- Is characterised by hypercellularity of the glomerular cells and basement Is characterised by hypercellularity of the glomerular cells and basement membrane thickening membrane thickening

- 2 forms: 2 forms: classical form classical form – proliferation of mesangial matrix with expansion to – proliferation of mesangial matrix with expansion to capillary walls between endothelium and BMcapillary walls between endothelium and BM

disease of dension depositsdisease of dension deposits – non-linear accumulation of material in – non-linear accumulation of material in lamina densa of the basal membranelamina densa of the basal membrane

- etiopathogenesisetiopathogenesis: ??? - association with infection (endocarditis, abscessus….): ??? - association with infection (endocarditis, abscessus….) - genetic faktors (HLA B8, DR3…) - genetic faktors (HLA B8, DR3…)

- Clinical syndrome:Clinical syndrome: nephrotic proteinuria with microhematuria, hypertension, nephrotic proteinuria with microhematuria, hypertension, anemia and decreased levels of the complements (anemia and decreased levels of the complements (C3)C3)

IgA nephropathy (Berger´s disease)IgA nephropathy (Berger´s disease)

• Mesangioproliferative GN with deposits of IgA, event. C3Mesangioproliferative GN with deposits of IgA, event. C3

• Etiology:Etiology: - unknown, clinical manifestation is associated with infection – - unknown, clinical manifestation is associated with infection –

with latent period 2-3 dayswith latent period 2-3 days

- association with HLA (DQ, DP)- association with HLA (DQ, DP)

T-lymphocytes produce T-lymphocytes produce levels of IL-2 (+ levels of IL-2 (+ IR-2R) and they IR-2R) and they

are constantly stimulateare constantly stimulate

production of IgA by B-lymphocytesproduction of IgA by B-lymphocytes

• Clinical manifestations:Clinical manifestations: asymptomatic hematuria - nephrotic syndrome asymptomatic hematuria - nephrotic syndrome

Chronic glomerulonephritisChronic glomerulonephritis

Common terminal result of many glomerular Common terminal result of many glomerular diseases diseases

(„end stage kidney“)(„end stage kidney“) It is charecterised by different degrees of It is charecterised by different degrees of

sclerotization and proliferationsclerotization and proliferation

PathogenesisPathogenesis: : damage (loss) of nephronsdamage (loss) of nephrons

hyperperfusionhyperperfusion

hyperfiltrationhyperfiltration

sclerosis of glomerulisclerosis of glomeruli

Glomerulopathy in connective tissue Glomerulopathy in connective tissue disordersdisorders

SLE predominantly affects women, who account for 90% casesSLE predominantly affects women, who account for 90% cases The age of onset is usually between 20 and 40 yearsThe age of onset is usually between 20 and 40 years Many different tissues and organs may be involved (the body produces Many different tissues and organs may be involved (the body produces

antibody against its own DNA), but renal involvement is the most antibody against its own DNA), but renal involvement is the most significant in terms of outcomesignificant in terms of outcome

Histologic pattern:Histologic pattern: WHO classification – WHO classification – normal glomerules (typ I)normal glomerules (typ I) - mezangial GN (typ II)- mezangial GN (typ II) - focal proliferative GN (typ III)- focal proliferative GN (typ III) - diffuse proliferative GF (typ IV)- diffuse proliferative GF (typ IV) - membranous GN (typ V) - membranous GN (typ V) - glomerular sclerosis (typ VI)- glomerular sclerosis (typ VI)

Systemic lupus erythematosisSystemic lupus erythematosis

VasculitisVasculitis

Heterogenous group of diseases characterised Heterogenous group of diseases characterised by necrotizing inflammation of vesselsby necrotizing inflammation of vessels

Etiology:Etiology: primary x secondary primary x secondary

Pathogenesis:Pathogenesis:

- damage by immunocomplexes- damage by immunocomplexes

- ANCA (pauciimmune form)- ANCA (pauciimmune form)

- damage by cells (IV. typ)- damage by cells (IV. typ)

Henoch-SchHenoch-Schöönlein purpuranlein purpura

- systemic vasculitis affecting medium-sized vesselssystemic vasculitis affecting medium-sized vessels

especially in children and younger peopleespecially in children and younger people It is frequently develops post-infections It is frequently develops post-infections

Clinical manifestationClinical manifestation: - non-trombocytopenic purpura : - non-trombocytopenic purpura - affect joints, serose membrane, GIT and- affect joints, serose membrane, GIT and glomeruliglomeruli alterations are similar to finding in IgA nephropathyalterations are similar to finding in IgA nephropathy

Polyarteritis nodosaPolyarteritis nodosa

- is an inflammatory and necrotizing disease involving the is an inflammatory and necrotizing disease involving the medium-sized and small arteries throughout the body. medium-sized and small arteries throughout the body.

- Men are more commonly affected than womenMen are more commonly affected than women

Etiopathogenesis:Etiopathogenesis: usually unknown usually unknown Clinical manifestationClinical manifestation: variable – general symptoms + : variable – general symptoms + specific symptomsspecific symptoms (skin, kidney, GIT, heart…)(skin, kidney, GIT, heart…)

Histologic patternHistologic pattern: focal glomerular sclerosis, crescents: focal glomerular sclerosis, crescents

Pauci-immune necrotizing GNPauci-immune necrotizing GN

Wegener´s granulomatosisWegener´s granulomatosis

- is a vasculitis leading to sinus, pulmonary and renal disease is a vasculitis leading to sinus, pulmonary and renal disease glomerulonephritisglomerulonephritis 90% of such patients have a positive ANCA90% of such patients have a positive ANCA ANCAANCA – – react with neutrophilsreact with neutrophils respiratory burst of phagocytic cellsrespiratory burst of phagocytic cells release of free radicalsrelease of free radicals degranulationdegranulation injury to endothelial cells injury to endothelial cells

Diabetic nephropathyDiabetic nephropathy= diabetic intracapillary glomerulosclerosis (sy Kimmelstielův-Wilsonův)= diabetic intracapillary glomerulosclerosis (sy Kimmelstielův-Wilsonův)

EtiopathogenesisEtiopathogenesis: : hyperglycemia affects conformation BM and mesangial matrixhyperglycemia affects conformation BM and mesangial matrix renal flow and glomerular pressurerenal flow and glomerular pressure (hyperfiltration)(hyperfiltration)

proliferation of cellsproliferation of cells thickness GMB with expansion of mesangiathickness GMB with expansion of mesangia glomerulosclerosisglomerulosclerosis

Clinical manifestationClinical manifestation: latent stage - asymptomatic: latent stage - asymptomatic incipient stageincipient stage manifest stage of diabetic nepropathymanifest stage of diabetic nepropathy chronic renal failure chronic renal failure

Schematic demonstration of running diabetic Schematic demonstration of running diabetic nephropathynephropathy

AmyloidosisAmyloidosis

Kidney belong to organs most frequently affected by amyloidosisKidney belong to organs most frequently affected by amyloidosis

ALAL amyloidosis – is a complication of myeloproliferative diseases (myelom, amyloidosis – is a complication of myeloproliferative diseases (myelom,

((primaryprimary) makroglobulinémie)) makroglobulinémie)

AAAA amyloidosis – is a complication of chronic inflammatory diseases (RA, amyloidosis – is a complication of chronic inflammatory diseases (RA,

((secondarysecondary) TBC, Crohn´s disease e.g.)) TBC, Crohn´s disease e.g.)

Clinical manifestationClinical manifestation: nephrotic syndrom, subsequently renal failure : nephrotic syndrom, subsequently renal failure developsdevelops

Hereditary nephropatiesHereditary nephropaties

Alport syndromAlport syndrom- Hereditar nephritis with deafness (X chromosome)Hereditar nephritis with deafness (X chromosome)

- PathogenesisPathogenesis: congenital defect of collag synthesis : congenital defect of collag synthesis

GMB very slight or with more layersGMB very slight or with more layers

GN focal (diffuse) proliferation with segmental sclerosisGN focal (diffuse) proliferation with segmental sclerosis

hematuria, proteinuria or renal failure (males)hematuria, proteinuria or renal failure (males)

Congenital nephotic syndromCongenital nephotic syndrom- AR heredityAR heredity

- Pathogenesis: Pathogenesis: defect of syntesis of basal membrane defect of syntesis of basal membrane

-- pronounced and non-selective proteinuriapronounced and non-selective proteinuria

Nephrotic syndrom from first weeks of the life --- renal failureNephrotic syndrom from first weeks of the life --- renal failure