肾小球疾病Glomerular Diseases

丁小强复旦大学附属中山医院

Pathological changes -- glomerular injury

Clinical manifestations --proteinuria / hematuria

Pathological changes -- glomerular injury

Clinical manifestations --proteinuria / hematuria

A group of diseases

Complicated causes & mechanisms

Various clinical manifestations

Different prognosisMultiple treatment

Complicated causes & mechanisms

Various clinical manifestations

Different prognosisMultiple treatment

• primary glomerular diseases

• secondary glomerular diseases

• hereditary glomerular diseases

Immune mechanismsHumoral

Cell-mediated

Immune mechanismsHumoral

Cell-mediated

Non-immune mechanismsNon-immune mechanisms

InflammationInflammation

Glomerular diseasesGlomerular diseases

A. Immune mechanisms

(A)deposits of Circulating Immuno-Complex (CIC)

circilation antigen+ antibody

CIC kidney CIC/deposits

antigen extrinsic drugs--nonhomologous serum, penicillin foods—xenogenic protein pathogen—specific serotypes streptococci,

HBV, HCV

intrinsic nucleus （ SLE) cytoplasm （ ANCA ） cellular membrane antigen of tumor antigen of thyroid

Why does CIC deposit in the glomeruli?

• Large area of glomerrular capillaries --more chances to contact

• Net structure of CIC --easy to deposit and settle down

• Clearance dysfunction of mesangial cells, disability of mononuclear macrophage, component or function defect of complements

Decrease clearance of CIC

(B)in situ Immunocomplex 1. Native renal antigen glomerular basement membrane + anti- glomerular basement membrane an

tibody (anti- glomerular basement membrane glomerul

onephritis)

2. Antigens trapped or planted DNA+ anti-DNA antibody (Lupus Nephritis)

Balance between the deposit and clearance of IC determines the

situation of the diseases

• Persistence of antigen

• Clearance dysfunction of mesangial cells

• disability of mononuclear macrophage

• component or function defect of complements

IC deposit > clearance

B. Cell-mediated immune mechanisms

minimal change glomerulopathy ?

C. Non –immune mechanisms

• glomerular hypertension• hyperlipidemia (LDL- Cho)• advanced glycosylation end products

(protein)

glomerulosclerosis

Inflammation• Mediators of inflammation

– A group of molecules which act as mediators of inflammation and complicated biological function

• Origin of inflammation mediators in kidney– Extrinsic Cells in kidney

• infiltrative neutrophil, lymphocyte, mononuclear macrophage , platelet

– Intrinsic cells in kidney• Mesangial cells, tubular cells, endothelial cells

Mediators of inflammation - active oxygen and active nitrogen - lipids - complements - cytokines - chemotatic factors - adhesion molecules - growth factors - vasoactive substances

To arouse or promote - proliferation of cells - accumulation of extracellular matrix - changes of histological structure - expression of immunomodulating mole

cules and adhension molecules

Effects of the inflammation mediators

Effects of the inflammation mediators

Mechanisms of Primary GNimmune non-immune

inflammationInflammatory cells

Extrinsic cells Intrinsic cells neutrophil, lymphcyte mesangial cells mononuclear macrophage epithelial cells platelet, tubular cells endothelial cells

Inflammation mediators cytokines TNF,IL-1 growth factors TGF,PDGF chemotatic factors MCP-1,IL-8 complements, vasoactive substances active oxygen and active nitrogen

Coagulation and fibrolysis system, enzyme

Glomerular injuries

Essential in the initiationEssential in the initiation

Essential in the progressive periodEssential in the progressive period

immune non-immune

initiation end stage Primary GN

Sites of pathological changes

Mesangium Mesangial cell

Mesangial matrixBasement membrane

PodocyteFoot processEndothelial cell

The peripheral portion of a glomerular lobule

Pathological changes• LM

– Mesangial cells, matrix of mesangium– Epithelial cells– Endothelial cells– Basement membrane– Loops of glomeruli

• EM – Foot process– Basement membrane– Hyperplasy of mesangium (electron-dense deposits )

• IF – Sites, appearances and types of the deposit (Ig or C)

Basical changes

•Proliferation

•Fibrosis and sclerosis

•Necrosis

•Infiltration of inflammatory cells

Extents of Injuries primary GN glomerular injuries—only

or dominating changes secondary GN glomerular injuries— a pa

rt of systematic diseases diffuse impaired glomeruli>50% focal impaired glomeruli <50% global impaired capillary loops of

a glomerule >50% segmental impaired capillary loops of

a glomerule <50%

Pathological types of primary GN

• Minimal change glomerulonephritis

• Focal segmental lesions

• Diffuse glomerulonephritis

• Unclassified glomerulonephritis

1. Minor Lesions of glomeruliNo specific lesionsLM—mild proliferation of mesangial cells and accumulation of ECMS

• minimal change disease ， MCD

• mild mesangial proliferative GN

• recovery stage of endocapillary GN

• others

MCD (left)normal ,(right) fusion & effacement of foot processes

2. Focal and Segmental Lesions

1) focal and segmental proliferative

glomerulonephritis

2) focal and segmental glomerulosclerosis

segmental glomerulonephritis

3. Diffusive glomerulonephritis

(1) membranous nephropathy －－ MN

(lesions in GBM)

MN (left) normal,(right)subepithelial deposits of IC(D), thickening of GBM,formation of spikes (S), fusion of foot processes

(2) proliferative glomerulonephritis

• mesangial proliferative GN

( lesions in mesangium)

– IgA nephropathy

– Non-IgA nephropathy

• domonating IgG deposit

• IgM nephropathy

MsPGN (left)normal, (right)proliferation of mesangial cells and matrix and electron-dense deposits (D)

• endocapillary proliferative GN ( lesions in mesangium & endo

thelial cells)

endocapillary proliferative GN (left) normal, (right) endothelial(E) & mesangial(M) cell proliferation and subepithelial humplike dense deposits(D)

• mesangiocapillary GN or membranoproliferative GN (lesions in mesangium & GBM)

• dense desposit GN (electron-dense deposits)

MmPGN (left) normal, (right) proliferation of mesngium (M),electron-dense deposits(D), and subendothelial mesangial cytoplasm interposition （ I ）

• crescentic GN or extracapillary GN

Crescentic GN (left) normal, (right) splitting of GBM, leakage of fibrin(F), proliferation of epithelial cells,(E), infiltration of mononuclear macrophages(P), formation of crescents

(3) sclerosing GN

4.unclassified glomerulonephritis

Characters of lesions in GN Proliferative changesProliferative changes

MsPGNMsPGN

IgANIgAN

IgMNIgMN

OthersOthers

Including segmental proliferativIncluding segmental proliferative GNe GN

MmPGNMmPGN

Crescentic GNCrescentic GN

Endocapillary proliferative GN

Proliferative changesProliferative changes

MsPGNMsPGN

IgANIgAN

IgMNIgMN

OthersOthers

Including segmental proliferativIncluding segmental proliferative GNe GN

MmPGNMmPGN

Crescentic GNCrescentic GN

Endocapillary proliferative GN

Non- proliferative changesNon- proliferative changes

FSGSFSGS

MCDMCD

MNMN

Non- proliferative changesNon- proliferative changes

FSGSFSGS

MCDMCD

MNMN

•Proliferation of mesangium can presents in varied types of GN

•Proliferation and subsequent stiffness of mesangium may be the results of varied types of GN

FSGS • primary--later-phase of the disease its

elf• secondary-- later-phase of other types

of GN•Crescents can presents in different types of GN

Clinical manifestations

Proteinuria– Urinary protein test — positive

– Urinary protein excretion rate 150mg/d

Charge barrier of glomerule1.Epithelial cells 2. GBM 3. Endothelial cells 4. Filtrated substances

Filtration barrier

mechanisms of production of proteinuria

机 制 性 质

肾小球滤过 肾小管重吸收 中、高分子 低分子

肾小球性蛋白尿

肾小管性蛋白尿

Moderate/high MW moleculesModerate/high MW molecules

mechanismsmechanismsmechanismsmechanisms molecular wieghtsmolecular wieghtsmolecular wieghtsmolecular wieghts

filtration from filtration from GlomeruliGlomerulifiltration from filtration from GlomeruliGlomeruli

Readsorption Readsorption from tululesfrom tululesReadsorption Readsorption from tululesfrom tulules

Low MW Low MW moleculesmoleculesLow MW Low MW moleculesmolecules

Glomerular proGlomerular proteinuriateinuria

Tubular proteiTubular proteinurianuria

Glomerular proGlomerular proteinuriateinuria

Tubular proteiTubular proteinurianuria

filtration barrierproperties charge- size- selective selective

Selective albumin impaired normalproteinuria (moderate MW molecules)

Non-selective albumin &proteinuria high MW proteins impaired impaired

* Mixed proteinuria: moderate/high MW or moderate/low MW;glomerular &tubular proteinuris

quantity

Mild < 1.5g/d

Moderate 1.5-3.5g/d

severe > 3.5g/d 或 50mg/kg/d

hematuria• RBC >3 个 /HP

(fresh, 10 ml sample, 1500rmp centrifuge for 5 min, sediment observation)

• gross hematuriaRed color of urine, 1ml blood /1L urine

hematuria RBC from glomeruli

squeezing through GBM

dismorphic RBC

Phase-contrastmicroscopy• dismorphic RBC>50 ％　　　 Hypothesis:glomerular bleeding• dismorphic RBC>70% Final diagnosis:glomerular bleeding 　　　　　

Urinary RBC volume distribution curve

•dissymmetry curve•MCV of urinary RBC<that in blood

Urinary RBC volume distribution curve

•dissymmetry curve•MCV of urinary RBC<that in blood

changing when passing tubules with different osmosis

changing when passing tubules with different osmosis

edema fluid retention in tissue spaces peripheral edema fluid retention in serous cavity 　 glomerular diseases

GFR 　　　 large amount of urinaryprotein lostIntrinsic RAS & Aldosterone hypoalbuminemia

water & sodium filtration 　 colloid osmotic pressure water & sodium readsorption

primary water & sodium retention 　 secondary water & sodium retention

Effective circulation blood volumn　 edema

Effective circulation blood volumn

Hypertension glomerular diseases

primary water & stimulus, such asischemiasodium retention

Volumn-dependent vessoconstrictive vessodilatory substances substances

　　　　　　　　 RAS,Ald PGI2,PGE2

vessoactive substances-dependent

　　　 Hypertension 　

Clinical types of GN

• Glomerulonephropathy • Confined concept

• leading manifestation: proteinuria, with/without hematuria

• Extensive concept• glomerular diseases ( disorders )

• Glomerulonephritis• leading manifestation: hematuria, with/without p

roteinuria

Nephrotic syndrome

1. Large-amount proteinuria > 3.5g/d

2. hypoalbuminemia 　 < 30g/L

3. edema

4. hyperlipidemia

1+2 ---essential

severe edemasevere edema hyperlipidemiahyperlipidemia

hypoalbuminemiahypoalbuminemia

Large-amount proteinuria

Large-amount proteinuria

Center

key

Essential for diagnosis

Intake of protein

Ingestion from GI

synthesis in liversynthesis in liver

lost through urineNS

lost through urineNS

consumptionconsumption

Mechanisms of hypoalbuminemiaMechanisms of hypoalbuminemia

Cl i ni cal mani festati on of GNmanifestation

initiation hematuria proteinuria edema,hypertension renal failure

GN急性 综合征 acute 100% 100% frequent resumabl eGN急进性 综合征 acute 100% 100% frequent ARF

GN慢性 综合征 latent frequent frequent frequent CRF

GN *隐匿性 综合征 latent frequent <1g/d (-) (-)

Linkage of clinical manifestation and pathological changes (1)

Pathological 　 proliferative non-proliferativechanges 　　　 MsPGN MCD　　　 MmPGN 　　　 MN*　　　 Endocapillary PGN FSGS Crescentic GN

Clinical hematuria － proteinuria － certain certain, sometimesManifestation nephritis syndrome nephrotic syndrome

　 proteinuria － hematuria － possible occasional * 　

Linkage of clinical manifestation and pathological changes (2) clinical pathological AGN endocapillary PGN possible NS RPGN crescentic GN possible NS CGN nephritis syndrome MsPGN 2 MmPGN 2 nephritis syndrome FSGS 2 +nephrotic syndrome MN2 NS MCD 1

Acute Glomerulonephritis

Etiology• Streptococcus -hemolytic streptococcus,

group A, type XII, nephritogenic strains•antigen

•components of cytoplasm & membrane•frequently CIC, sometimes ‘planted antigen’

• Others• other bacteria, such as staphylococcus epidermidis• viruses• parasites

Pathological changes• Endocapillary Proliferative GN

• Acute phase

• Proliferation of endothelial & mesangium

• Recovery phase

• Only mesangium proliferation, sometimes minor lesion

Clinical Manifestation

1.Epidemiology: primarily children, sometimes adults & the aged

2. Preliminary infection

frequently tonsillitis,upper respiratory infectionLatent period:1-3 w

occasionally skin infectionLatent period:longer,but less than 4w

3.Nephritis syndrome(1)hematuria 100% ， 40% are gross hematuria(2)proteinuria frequent ， <20% are nephrotic syndrome(3)edema >90%(4)hypertension 80%(5)renal failure mild,acute renal failure

4.Laboratory findings (1) acute phase of infection of Strep.

•elevated ASO titer (some Strep. No hemolysin O)•only the marker of infection, not nephriti

s(2) acute phase of immune reactions

•serum C3 & total complements,return to normal within 8w

•blood CIC

Natural History• edema and hypertension

– disappear in one month

• hematuria, proteinuria– usually reduce in one month, resolve within

2 to 3 months– some resolve within 6 to 12 months

• C3

– return to normal in two months

DiagnosisPoints• preliminary infection &latent period• acute onset• surely hematuria, frequently edema and hypert

ension

• ASO , C3 —— dynamic change

• Self-limitation

Differential DiagnosisDiseases presented with acute nephritis syn

drome• GN secondary to infection of other pathogens

– other bacteria, viruses (Varicella-zoster virus, EB, influenza virus)

– Climax of infection or within 5 days

– Mild abnormal of urine examination

– Hypertension and edema are unusual

– Normal blood complement level

• rapidly progressive GN

• CGN

• systemic diseases

lupus nephritis

Schönlein-Henoch purpura

Indications of kidney biopsy

• Oligouria > 1w ， except ECBV insufficie

nt, urinary tract obstruction, etc

• Progressive renal failure

• Unresolved in 2 months

• untypical manifestation, or with nephroti

c syndrome

Treatment1.Supportive treatment• Rest• Food & water

•Restrictive intake of•NaCl <5 g/d

• if moderate to severe edema or hypertension•Water

• if decreased urine volume •Protein

• Renal failure, but not dialysis yet

2.Treatment of infection• Penicilin for 2 w• Tonsillectomy– if recurrent attacks

of tonsillitis1) patient’s condition is stable, Upr

o<1g/d, URBC < 10/HP2) Penicilin for 2 wks before and after th

e surgery

3. Symptomatic treatment• Diuresis• Antihypertension• Dialysis

Prognosis• hematuria, proteinuria

–usually reduce in one month, resolve within 2 to 3 months–some resolve within 6 to 12 months

• 1%ARF Death

• 6%-18% CGN?

Rapidly progressive glomerulonephritisRPGN

•Rapidly progressive nephritis syndrome

•Some induced by respiratory infection

•Acute onset, rapidly progressive

•Renal failure within a few weeks to a few mont

hs

1.primary RPGN Crescentic GN2.other primary GN other pathological changes with lots of crescents3.secondary RPGN SLE, SHP, etc

RPGN Type I Type II Type III

anti-GBM IC Pauci-immuneIF linear GBM Granular GBM （ - ） deposits & mesangium deposits anti-GBM AB （ + ） C3 、 CIC 70%-80% small vessel vasculitis ANCA （ + ） the young & the middle-aged the middle-aged middle aged & aged & aged

Most frequently in ChinaMost frequently in China

Diagnosis

• Acute onset

• Rapidly progressive

• Renal failure within a few weeks to a few months

• Acute renal failure Chronic renal failure

Differential Diagnosis Rapidly progressive nephritis syndrome ——not primary RPGN

- other primary GN AGN, IgAN, etc - secondary GN Goodpasture Syndrome, LN, SHP * accompanied by crescentic GN * severe pathological changes

Diseases with ARF• ATN• AIN - definite etiology -obsolete proteinuria and hematuria - specific manifestation ATN——large quantity of renal tubular epithelial cells

in urine AIN——hypersensitiveness (rashes, fever, arthralgia)

Treatment EARLY!!!

• Aim to humoral immune mechanisms

1.plasmapheresis discard the antibodies plasm exchange immoadsorption type I, III 2.drugs glucocorticoid +cytotoxic drugs MP0.5-1.0g/d3 ， repeat if necessary

CTX type II, III

symptomatic treatment

• renal failure– balance of fluid, electrolytes and acid-base– dialysis

• infection

• hypertension

Prognosis

Hardly relieve mostCRF or death

Risk factors

Type I-worst,II-worse,III-bad

Treatment not progressive & prompt

Age the aged

Chronic Glomerulonephritis

Manifestation chronic nephritis syndrome

Pathological changes except MCD,MmPGN, Crescentic GN

Clinical manifestation 1.age any age, frequently young 2.preliminary infection upper respiratory tract, intestinal tract latent period < 1 wk 3.nephritis syndrome

Hematuria,proteinuria,edemaHematuria,proteinuria,edema

Hypertension,renal failureHypertension,renal failure

uremiauremia

4.Prognosis factors (1)pathological properties (2)treatment (3)hypertension (4)infection,prerenal factors (hypotension etc) (5)nephrotoxic drugs

Points of Diagnosis

• chronic onset• proteinuria and/or hematuria• protracted and progressive

Differential Diagnosis

CGN

Differential DiagnosisDifferential Diagnosis

1. AGN AGN CGN age children young&middle-aged preliminary infection frequently sometimes latent period 1-3w <1w onset acute chronic, insidious hematuria 100% sometimes no edema frequently sometimes no hypertension frequently sometimes no ASO frequently normal blood C3 frequently , persistent/normal return within 8wks prognosis resolved within 1yr protracted and progressive pathology MmPGN/MsPGN

2.Essential hypertensive nephrosclerosis

EHT CGNfirst present hypertension abnormal urinefunction injury in advance tubule glomerulehematuria occasionally frequentlynephrotic proteinuria occasionally frequentlysystemic hypertension manifestationheart, eyeground compared with kidney equal milder pathology arteriolar sclerosis

3.secondary GN SLE (1)systemic presentation (2)immune abnormolity(C,self-AB) (3)pathological changes

SHP (1)purpura (2)stomach, joint

Chronic pyelonephritis CPN CGN mechanisms infection immunesites pelvis,calices,tubule glomerulepresents of infection + Upro excretive /tubular glomerularURBC non-glomerular glomerularhypertension infrequently frequentlyedema infrequently frequentlykidney lesions tubule glomeruledysmorphosis one side two side

TreatmentTarget inhibit immune reaction halt the progression of disease

1.restrictive intake of protein

<0.5-0.8g/kg/d

protein of high biological value

pressure in glomeruli

2.Antihypertension less than 140/90mmHg ， ideal target 125/83mmHg

dialation of efferent glomerular arteriole > dialation of afferent glomerular arteriole

pressure in glomeruli Upro

postpone glomerulosclerosis

ACEI/ARBACEI/ARB

3.anti-platelet

4.immunosupression

Clinical manifestation 1.Characteristics

(1)large quantity of Upro

(2)severe edema

(3)hypoalbuminemia

(4)hyperlipidemia

Nephrotic SyndromeNephrotic Syndrome

2.Others (1) thrombosis & embolism

renal veins or inferior vena cava 25% (2)infection (3)acute renal failure•Blood volumeperfusion of kidneys ischemia of kidneys, tubule necrosis•Severe glomerular lesions

•crescent formation•Severe proliferation of mesangium•Necrosis of capillary loops

•Nephrotoxic drugs•idiopathetic

1.among varied types of pathology 2.between secondary GN

（ 1 ） SLE（ 2 ） SHP（ 3 ） DN history, hematuria, pathological changes（ 4 ） amyloidosis

history of chronic infection,systemic lesions (heart, liver, GI, tongue), pathological changes (kidney, tongue, rectum)

（ 5 ） MM Middle-aged/aged, ostalgia, osteonecrosis(X-ray, isotope scanning), abnormal protein (blood single-peak protein, blood and urine light chain protein,urine BJ protein)

Diagnosis & Differential DiagnosisDiagnosis & Differential Diagnosis

1. Supportive treatment 1. rest 2. Food and water (1) water & sodium restriction when with severe edema (2) protein 1-1.2g/kg/d (3) lipid restriction when with hypoalbuminemia (4) energy 30-35 Kal/kg/d

TREATMENTTREATMENT

2. symptomatic treatment 1. diuresis osmotic diuretics plasma colloid osmotic pressure tubule fluid osmotic pressure

fluid transmit from tissue readsorption of water space to blood vessels

blood volume diuretics

mannitol, dextran, albuminmannitol, dextran, albumin

diuresisdiuresis

2. Aim to proteinuria

ACEI/ARB

3. Major treatment 1. glucocorticoid mechanisms (1)immuosupression (2)anti-inflammation principles (1)sufficient dose when initiation 0.8-1.2g/kg/d reduce 2wks after Upro is negative *if Upro doesn’t reduced apparently in 8-12wksineffective (2) reduce the dose slowly 10%/2-3wks (3) sustaining treatment minimal dose:10-15mg/d ， >6m-1y

Sensitivity of glucocorticoid

1mg/kg/d 8w

negative Upro positive

relapse when reduce to some dosage

Sensitivity of glucocorticoid

1mg/kg/d 8w

negative Upro positive

relapse when reduce to some dosage

sensitive sensitive

dependentdependent

ineffectiveineffective

2. immunosuppressive agents

• cytotoxic drugs alkylating agent—CTX, chlormethine, CB1348 inhibit duplication of DNA• Aza,MMF inhibit synthesis of RNA inhibit proliferation of B lymphocyte • CyA inhibit synthesis of L-2 inhibit proliferation of T lymphocyte

indications

• glucocorticoid dependent or ineffective• glucocorticoid untolerated

4. Treatment of complications

• anticoagulation, thrombolysis

• anti-infection

• balance of electrolyte