disease of the urinary system - zhejiang...

Pathology Department, Zhejiang University School of Medicine,

马丽琴，[email protected]

Disease of the Urinary System

Disorders of the Kidney

Congenital – Malformations, cysts, dysplasia.

Acquired– Glomerular diseases– Tubulointerstitial diseases– Neoplasms – carcinoma

GlomerularGlomerular DiseasesDiseases((Glomerulonephritis,GNGlomerulonephritis,GN))

GLOMERULONEPHRITISGLOMERULONEPHRITIS

Definition Classification Pathogenesis Histologic Alterations Clinical Manifestations

Primary GNAcute diffuse proliferative glomerulonephritis

Rapidly progressive (crescentic) glomerulonephritis

Membranous glomerulopathyMinimal change diseaseFocal segmental glomerulosclerosisMembranoproliferative glomerulonephritisIgA nephropathyChronic glomerulonephritis

Secondary GNSystemic lupus erythematosusDiabetes mellitusAmyloidosisGoodpasture syndromeMicroscopic polyarteritis/polyangiitisWegener granulomatosisHenoch-Schönlein purpuraBacterial endocarditis

Immune MechanismsImmune MechanismsAntibody-Mediated InjuryCytotoxic AntibodiesCell-mediated Immune InjuryActivation of Alternative Complement Pathway

In Situ Immune Complex Deposition Circulating Immune Complex Deposition

PATHOGENESIS OF GLOMERULAR INJURY

HypercellularityHypercellularity

Basement Membrane Thickening/brokenBasement Membrane Thickening/broken

Hyalinization Hyalinization

Sclerosis Sclerosis

Exudation /necrosisExudation /necrosis

Change of Change of stromastroma

BASIC HISTOLOGIC ALTERATION

HypercellularityHypercellularity

Cellular proliferation of mesangial, endothelial,or epithelial cells

Leukocytic infiltration

Formation of crescents

Basement Membrane ThickeningBasement Membrane Thickening

Thickening of the capillary walls

Deposition of amorphous electron- dense material

Thickening of the basement membrane

proper

Hyalinization and SclerosisHyalinization and Sclerosis

Accumulation of material that is homogeneous and eosinophilic by light microscopy

A consequence of capillary wall injuryThe end result of various forms of glomerular damage

GlobalGlobal

SegmentalSegmental

Pathological DiagnosisPathological Diagnosis

LM （光学显微镜检查）

EM （电子显微镜检查）

IF （免疫荧光显微镜检查）

Clinical Manifestations

Syndromes

Proteinuria

Hematuria

Edema

Hypertension

Azotemia

Uremia

Features

Hypoproteinemia

Hyperlipidemia

Oliguria

Anuria

PolyuriaNocturiaIsosthenuria

CLINICAL MANIFESTATIONS

Acute nephritic syndrome

Rapidly progressive nephritic syndrome

Chronic nephritic syndrome

Nephrotic syndromeAsymptomatic Hematuria or Proteinuria

MAJOR PRIMARY GN

Acute Postinfectious GN Rapidly Progressive GN Membranous Nephropathy Minimal-change Disease Membranoproliferative GN IgA Nephropathy Chronic GN

Overview

Pathogenesis

Morphology

Treatment and Prognosis

Clinical Features

ACUTE POSTINFECTIOUS GN

Endocapillary Proliferative GN

Acute Diffuse Proliferative GN

Postinfectioous GN


Appears usually 1-4 weeks after a group A -hemolytic streptococcal pharyngeal or skin infection

Occurs most frequently in children 6-10

years old

Characterized histologically by diffuse

proliferation of glomerular cells with infiltration of leukocytes


Caused by deposition of immune complexes Ag may be exogenous or endogenous


Enlarged glomeruli-”diffuse”

Hypercellularity: proliferation of glomerular cells & infiltration by WBC’s

Compression of glomerular capillary lumina

Proliferation of mesangial cells & endothelial cells


Electron dense deposits – subepithelial “humps”

Granular deposits of IgG, IgM & C3 in the mesangium & along the GBM


Subepithelial “humps”

EM

Acute Nephritic Syndrome

Mesangial cells Endothelial cells


Overview

Pathogenesis

Morphology


Clinical Features

RAPIDLY PROGRESSIVE GN

Extracapillary Proliferative GN

Crescentic GN

Malignant GN


Not a specific etiologic form of glomerulonephritis

Characterized clinically by rapid &

progressive loss of renal function with severe oliguria


Death from renal failure within weeks to months if untreated

Divided into 3 groups based on

immunologic findings


TYPE I RPGN Idiopathic Goodpasture syndrome

TYPE II RPGN Idiopathic Postinfectious Systemic lupus erythematosus Henoch-Schönlein purpura (IgA) Others


TYPE III RPGN (pauci-immune) ANCA associated Idiopathic Wegener granulomatosis Microscopic polyarteritis nodosa


Crescent formation by proliferation of parietal cells,

infiltrates of WBC’s & fibrin deposition in Bowman’s space

EM reveals focal disruptions in

the GBM


Patients present Rapidly progressive nephritic syndrome with acute nephritic syndrome, occasionally have the nephrotic syndrome

ANCA, anti-GBM & antinuclear Ab’s are

helpful in Dx


Overview

Pathogenesis

Morphology


Clinical Features

MEMBRANOUS NEPHROPATHY

Main cause of nephrotic syndrome in adults Characterized by diffuse thickening of the GBM

& the accumulation of electron-dense, immunoglobulin-containing deposits


Primary membranous GN is caused by autoantibodies directed against an Ag on the visceral epithelial cells

Secondary membranous GN is caused

by deposition of immune complexes


Diffuse thickening of glomerular capillary wall EM reveals subepithelial deposits Spikes can be seen by silver stains Granular deposits of Ig’s & complements on IF

GBM becomes progressively thicker and

compresses the capillary lumens


Nephrotic Syndrome

Massive proteinuria

3.5 gm/day

Hypoalbuminemia, plasma albumin levels

< 3 gm/dl Generalized edema Hyperlipidemia & lipiduria


Nephrotic Syndrome

Derangement in glomerular capillary walls which results in

permeability to plasma

proteins Complications:

infections due to loss of Ig’s &

complement

thrombosis due to loss of anticoagulant

factors


MAJOR PRIMARY GN

Overview

Pathogenesis

Morphology


Clinical Features

MINIMAL-CHANGE DISEASE

Lipoid nephrosis

Minimal Change Glomerulonephritis


Peak incidence 2-6 years of age Main cause of nephrotic syndrome in children

Characterized by diffuse effacement of foot

processes of podocytes

Sometimes follows a respiratory infection or

vaccination

Incidence in patients with Hodgkin disease


Evidence indicates an immune mechanism Immune dysfunction circulating cytokine injures visceral epithelial cells proteinuria

Some cases are caused by mutations in genes that encode slit diaphragm proteins


Glomeruli are normal by LM Proximal tubular cells are often laden with lipid

Epithelial cells exhibit diffuse loss of foot

processes on EM No Ig or complement deposits detected by IF


Nephrotic Syndrome


Overview

Pathogenesis

Morphology


Clinical Features

MEMBRANOPROLIFERATIVE GN

Mesangiocapillary Glomerulonephritis

(MPGN)



Characterized by alterations in the GBM, proliferation of glomerular cells & leukocyte infiltration

Accounts for 10-20% of cases of nephrotic

syndrome in children & young adults


Often present with a combined nephritic/nephrotic picture


Type I MPGN

Deposition of immune complexes with activation of both classical & alternative complement pathways


Type II MPGN

serum C3, factor B & properidin but

normal serum C1 & C4 activation of alternative complement pathway

> 70% of patients have C3 nephritic

factor (C3NeF)


Glomeruli are enlarged, hypercellular & lobulated

Glomerular capillary wall has a “double

contour” or “tram-track” appearance caused by duplication of the GBM with mesangial & monocyte interposition


Type I MPGN Subendothelial electron-dense deposits

Granular deposits of C3 and often IgG,

C1q & C4


Type II MPGN

Lamina densa is extremely electron-dense

(dense-deposit disease)

C3 is present in the GBM & mesangium

(mesangial rings) IgG, C1q & C4 are usually absent


10-20% of cases of nephrotic syndrome in children & young adults

A combined nephritic/nephrotic picture

Overview

Pathogenesis

Morphology


Clinical Features

IgA NEPHROPATHY

IgA NEPHROPATHY

Berger Disease

Characterized by presence of prominent deposits of IgA in the mesangium Most common type of GN worldwide

IgA NEPHROPATHY

Abnormality of immune regulation

mucosal IgA synthesis in response to

respiratory or GI exposure to environmental antigens

IgA & IgA immune complexes are entrapped in the mesangium activation of alternative complement pathway glomerular injury

IgA NEPHROPATHY

Considerable variation on LM: glomeruli may appear normal, may exhibit mesangioproliferative GN, focal proliferative GN or rarely crescentic GN

IF reveals mesangial deposition of IgA, often

with C3 & properdin, early complement components are absent

IgA NEPHROPATHY

Affects children & young adults Present with hematuria often after a

respiratory infection

Overview

Pathogenesis

Morphology


Clinical Features

CHRONIC GN

CHRONIC GN

End-stage Renal Disease Granular Contracted Kidney

Chronic Sclerosing GlomerulonephritisChronic Nephritis

CHRONIC GN

The kidneys are symmetrically small. The outer surface is diffusely granular.

On section, the cortex is thin and there is

increase in peripelvic fat.

Gross

CHRONIC GN

There is hyaline obliteration (hyalinization) of most of the glomeruli.

The glomeruli remaining undergo

compensatory hypertrophy & tubular dilatation Arterial & arteriolar sclerosis Interstitial chronic inflammation and fibrosis

Histological

CHRONIC GN

Chronic Renal Failure

Glomerular Pathology

Disease

Most Frequent Clinical

PresentationPatho-

genesisLight

Microscopy

Fluore- scence

MicroscopyElectron

MicroscopyPost- streptococcal glomerulonephritis

Acute nephritis

Antibody mediated; circulating or planted antigen

Diffuse proliferation; leukocytic infiltration

Granular IgG and C3 in GBM and mesangium

Sub- epithelial humps

Idiopathic RPGN

Rapidly progressive glomerulonephritis

Anti-GBM antibody Immune complex ANCA- associated

Proliferatio n; focal necrosis; crescents

Linear IgG and C3 Granular IgG or IgA or IgM Negative or equivocal

No deposits Deposits may be present No deposits


Disease


PresentationPatho-

genesisLight

Microscopy

Fluore- scence

MicroscopyElectron

MicroscopyMembra- nous glomerulo- pathy

Nephrotic syndrome

In situ antibody- mediated; antigen unknown

Diffuse capillary wall thickening

Granular IgG and C3; diffuse

Sub- epithelial deposits

Minimal change Disease

Nephrotic syndrome

Unknown, loss of glomerular polyanion; podocyte injury

Normal; lipid in tubules

Negative Loss of foot processes; no deposits


Disease


PresentationPatho-

genesisLight

Microscopy

Fluore- scence

MicroscopyElectron

MicroscopyMembrano- proliferative glomerulonephritis (MPGN) Type I

Nephrotic syndrome

(I) Immune complex

Mesangial proliferation; basement membrane thickening; splitting

(I) IgG + C3; C1q + C4

(I) Subendo- thelial deposits

Dense deposit disease (MPGN Type II)

Hematuria Chronic renal failure

(II) Auto- antibody: alternative complement pathway

(II) C3 ± IgG; no C1q or C4

(II)Dense deposits


Disease


PresentationPatho-

genesisLight

Microscopy

Fluore- scence

MicroscopyElectron

MicroscopyIgA nephropathy

Recurrent hematuria or proteinuria

Unknown; see text

Focal proliferative glomerulonephritis; mesangial widening

IgA +/- IgG, IgM, and C3 in mesangium

Mesangial and paramesan- gial dense deposits

Chronic glomerulonephritis

Chronic renal failure

Variable Hyalinized glomeruli

Granular or negative

TubulointerstitialTubulointerstitial NephritisNephritis

Infections

Toxins

Metabolic Diseases

Physical Factors

Neoplasms

Immunologic Reactions

Vascular Diseases

Miscellaneous

Causes of Tubulointerstitial Nephritis Infections

Toxins

Metabolic Diseases

Physical Factors

Neoplasms

Immunologic Reactions

Vascular Diseases

Miscellaneous

Pyelonephritis

Interstitial diseases induced by drugs

PYELONEPHRITISPYELONEPHRITIS

Definition Etiology & Pathogenesis Two Forms of

Pyelonephritis

Tubules, Interstitium & Renal Pelvis

Bacteria

Suppurative inflammation

PYELONEPHRITISPYELONEPHRITISDefinition

Bacterial infection

G¯ bacilli（E coli）

Etiology & Pathogenesis

Hematogenous infection Ascending infection

Pathways:

Predisposing Factors

Systemic

Local Urinary tract obstruction Urinary tract mucosa injury Vesicoureteral reflux

Etiology & Pathogenesis

Defense mechnisms

ACUTE PYELONEPHRITISACUTE PYELONEPHRITIS

CHRONIC PYELONEPHRITISCHRONIC PYELONEPHRITIS

Two Forms of Pyelonephritis

MorphologyACUTE PYELONEPHRITIS

Patchy interstitial suppurative inflammation Intratubular aggregates of neutrophils Tubular necrosis

LM

Acute pyelonephritis marked by an acute neutrophilic exudate within tubules and the renal substance.

ACUTE PYELONEPHRITIS

Renal papillary necrosis Perinephric abscesses Pyonephrosis

CHRONIC PYELONEPHRITIS

Chronic reflux-associated Chronic obstructive


Morphology

Asymmetric, irregularly scarred kidneys

Dilated, blunted or

deformed calycesThe pelvic mucosa is thickened & may be focally ulcerated.


LM The interstitium： Chronic inflammation The tubules：

Atrophy, necrosis & fibrosis Hypertrophy or dilation

May be filled with pink proteinaceous material (colloid

casts, thyroidization).

The calyceal mucosa: Chronic inflammation The glomeruli：periglomerular fibrosis

glomerular fibrosis & hyaline change

Chronic Course

Progression to azotemia and uremia


MALIGNANT TUMORSMALIGNANT TUMORS

Renal Cell Carcinoma

Nephroblastoma

Transitional Cell Carcinoma Of The Bladder

Nephroblastoma

Transitional cell carcinoma of the bladder

disease of the urinary system - zhejiang...

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