4th May Session 2 (a) Yasuhiko Tomino

8/18/2019 4th May Session 2 (a) Yasuhiko Tomino

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Yasuhiko Tomino, M.D.Yasuhiko Tomino, M.D.


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Session 2Session 2 -- NephritisNephritis

Primary glomerulonephritisPrimary glomerulonephritis

-- An overviewAn overview--

Yasuhiko Tomino, M.D.Yasuhiko Tomino, M.D.ProfessorProfessor

Division of Nephrology,Division of Nephrology,

Department of Internal Medicine,Department of Internal Medicine,

JuntendoJuntendo University School of MedicineUniversity School of MedicineTokyo, JapanTokyo, Japan


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What medical examinations do patientsWhat medical examinations do patients

with albumin and/or blood in their urine undergo?with albumin and/or blood in their urine undergo?

PatientPatient

Flow chart for patientsFlow chart for patients

Clinical diagnosisClinical diagnosis

TreatmentTreatment

Definite diagnosisDefinite diagnosis

AdmissionAdmission

1.1. UrinalysisUrinalysis/Urine culture/Urine culture

2. Blood pressure measurement2. Blood pressure measurement

3. Blood chemistry :3. Blood chemistry : BUN,BUN, creatininecreatinine, uric acid, uric acidNa, K,Na, K, ClCl, Ca, Pi, T, Ca, Pi, T--Pro(Alb),Pro(Alb),

TC,TG, ASO, ASK, IgA,TC,TG, ASO, ASK, IgA, IoGIoG,,IgMIgM, C3, C4, CH, C3, C4, CH5050, etc, etc

4. Renal function tests : GFR, RPF,4. Renal function tests : GFR, RPF, FishbergFishberg etc.etc.

5. Image analyses : IVP, Echo, CT, MRI etc5. Image analyses : IVP, Echo, CT, MRI etc

6.6.

Renal biopsyRenal biopsy


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Patients are clinically diagnosed as having one of fivePatients are clinically diagnosed as having one of five

syndromes by urinalysis and other examinationssyndromes by urinalysis and other examinationsCLINICAL SYNDROMES

Acute Nephritic SyndromeAcute Nephritic Syndrome

Definition : A syndrome characterized by abrupt onset of

hematuria, proteinuria, hypertension, decreased glomerular filtration

and retention of sodium and water.Rapidly Progressive Nephritic SyndromeRapidly Progressive Nephritic Syndrome

(Rapidly Progressive Glomerulonephritis)(Rapidly Progressive Glomerulonephritis)

Definition : Abrupt or insidious of hematuria, proteinuria, anemia

and rapidly progressive renal failure.

Recurrent or persistentRecurrent or persistent HematuriaHematuriaDefinition : Insidious or abrupt onset of gross or microscopic hematuria

with little or no proteinuria and no evidence of other features of the

nephritic syndrome.

Chronic Nephritic SyndromeChronic Nephritic Syndrome

Definition : Slowly developing renal failure associated with proteinuria,hematuria and hypertension.

NephroticNephrotic SyndromeSyndrome

Definition : A syndrome of massive proteinuria, edema, hypoalbuminemia

and frequently, hypercholesterolemia. Associated with a great variety of

glomerular lesions.

GLOMERULAR

DISEASES

( WHO CLASSIFICATION )( WHO CLASSIFICATION )


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Purposes of renal biopsyPurposes of renal biopsyto perform the definite diagnosisto perform the definite diagnosis

to determine the pathogenesisto determine the pathogenesis

to determine the prognosisto determine the prognosis

to decide the treatmentto decide the treatment


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Incidence of primary glomerulonephritis (GN) inIncidence of primary glomerulonephritis (GN) in JuntendoJuntendo

UniversityUniversity(1978(1978--2000)2000)

PGN (non-IgA ) 167 17.7%

Crescentic GN 11 1.2%IgA nephropathy 478 50.5%

MN 134 14.2%

MPGN 17 1.8%TBM disease 41 4.3%

MCNS 41 4.3%

FGS 37 3.9%IgM nephropathy 8 1.0%

Sclerosing GN 12 1.3%

Total 946


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Correlation of clinical presentations withCorrelation of clinical presentations with histologichistologic appearanceappearance

Leendert A. Van Es : Immunoglobulin A nephropathy.

Immunologic Renal Diseases, 1996.


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Pathogenesis of glomerulonephritisPathogenesis of glomerulonephritis


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ImmuneImmune--complex depositedcomplex depositedregions in aregions in a glomerulusglomerulus


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GlomerulusGlomerulus

Typical diseases :Typical diseases : GoodpastureGoodpasture SyndromeSyndrome

RPGNRPGN

Diabetic NephropathyDiabetic Nephropathy

fine granularfine granular

Typical disease : Membranous NephropathyTypical disease : Membranous Nephropathy

fine granular, coarse granularfine granular, coarse granular

Typical diseases : IgA NephropathyTypical diseases : IgA Nephropathy

MPGNMPGN

lumpy, bumpylumpy, bumpy

Typical disease : FGSTypical disease : FGS

linearlinear

Pattern ofPattern of immunofluorescentimmunofluorescent stainingstaining


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Basic patterns ofBasic patterns of immunofluorescenceimmunofluorescence in the kidneyin the kidney

Leendert A. Van Es : Immunoglobulin A nephropathy.



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IgGIgG

AntiAnti--GBM antibody mediated GNGBM antibody mediated GN


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PAS stainingPAS staining


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FibrinogenFibrinogen


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EM: Thickness of GBM; less than 200 nm (normal range; 300EM: Thickness of GBM; less than 200 nm (normal range; 300--400 nm)400 nm)

Recurrent orRecurrent or persistentpersistent hematuriahematuria


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MNMN


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IgGIgG


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PAM stainingPAM staining


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AGNAGN


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C3C3


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EMEM


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PAS staining MPGNPAS staining MPGN


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PAM staining

MPGN


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EMEM


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EMEM


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IgAIgA C3C3IgA nephropathy


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EMEM


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Initiation of IgA nephropathyInitiation of IgA nephropathyAntigenAntigen

Virus, Fungus, Bacteria,Virus, Fungus, Bacteria,

Food,Food,

IgGIgG,, IgMIgM, IgA1,fibronectin,, IgA1,fibronectin,lamininlaminin

IgA(IgA1)IgA(IgA1)--ICIC

alteration of molecules in the hinge regionalteration of molecules in the hinge region

of IgA (IgA1)of IgA (IgA1)

AntibodyAntibody

Aggregated IgA1Aggregated IgA1((nephritogenicnephritogenic IgA1)IgA1)

••PinocytosisPinocytosis

••ChargeCharge••CytokineCytokine

••ComplementComplement

••FcaR FcaR , novel, novel FcaR FcaR

••FcamR FcamR ••ASGPR ASGPR

••plgR plgR

••TransferrinTransferrin R R

IgA deposition inIgA deposition in mesangialmesangial areas/cellsareas/cells

G e n e t i c

f a c t or s

G e n e t i c

f a c t or s

Trigger ? Genetic ?Trigger ? Genetic ?

antigen antibodyantigen antibody--dependentdependent antigen antibodyantigen antibody--independentindependent

Receptors


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Leendert A. Van Es :

Immunoglobulin A nephropathy.



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Progression of IgA nephropathyProgression of IgA nephropathy

IgA deposition inIgA deposition in mesangialmesangial areas/cellsareas/cells

G e n e t i c

f a c t or s

G e n e t i c

f a c t or s

Cell infiltrationCell infiltration

Cytokine,Cytokine, chemokinechemokine and growth factorand growth factor

ROS (reactiveROS (reactive oxigenoxigen species)species)

Complement (local production)Complement (local production)

Platelet aggregation/Blood coagulationPlatelet aggregation/Blood coagulation

Adhesion moleculeAdhesion molecule

MesangialMesangial expansionexpansion

PodocytePodocyte damagedamage Cell proliferationCell proliferation

ProteinuriaProteinuria

TubularTubular

damagedamage

ChemokineChemokine

CytokineCytokine

TransferrinTransferrin

ComplementComplement

FcRnFcRn ((IgGIgG))

ESRFESRF

Interstitial damageInterstitial damageTubuloTubulo-- interstitial interstitial

CrossCross--talk talk

RepairRepair

macrophage, lymphocyte,macrophage, lymphocyte,

mast cell, fibroblastmast cell, fibroblast

??

??

resultresultcausecause

(activation)(activation)

ApoptosisApoptosis

GlomeruloGlomerulo-- tubular tubular

CrossCross--talk talk


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•• Lack ofLack of podocytepodocyte proliferationproliferation

•• Direct injury ofDirect injury of podocytepodocyteApoptosisApoptosis

•• Detachment ofDetachment of podocytepodocyte from thefrom the

glomerular basement membraneglomerular basement membrane(GBM)(GBM)

PodocytePodocyte injuryinjury


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Loss of charge barrier and/orLoss of charge barrier and/or

podocytepodocyte ((PodocytopeniaPodocytopenia and diseaseand disease

Severity in IgA nephropathy.Severity in IgA nephropathy.

LemleyLemley KV et al. KidneyKV et al. Kidney IntInt 20022002))

Causes of proteinuria/Causes of proteinuria/

albuminuriaalbuminuria

AlbuminAlbumin

Loss of size barrierLoss of size barrier

(damage of GBM)(damage of GBM)

Endothelial injury


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Normal Renal Tissue: PAS stainingNormal Renal Tissue: PAS staining


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EMEM


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PEI stainingPEI stainingNormal anionicNormal anionic

chargecharge


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PEI stainingPEI stainingMCNS: lack MCNS: lack

of anionic chargeof anionic charge


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FSGSFSGS


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IgMIgM


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Kidney Blood Press Res 2001;24:99Kidney Blood Press Res 2001;24:99--104104

ToshimasaToshimasa HishikiHishiki, Isao, Isao ShiratoShirato, Yutaka Takahashi, Kazuhiko, Yutaka Takahashi, Kazuhiko FunabikiFunabiki,,

SatoshiSatoshi HorikoshiHorikoshi and Yasuhiko Tominoand Yasuhiko Tomino

Division of Nephrology, Department of Internal Medicine,Division of Nephrology, Department of Internal Medicine, JuntendoJuntendo University School of Medicine,University School of Medicine,

Tokyo, JapanTokyo, Japan

Original PaperOriginal Paper

PodocytePodocyte Injury Predicts Prognosis inInjury Predicts Prognosis in

Patients with IgA Nephropathy Using aPatients with IgA Nephropathy Using a

Small Amount of Renal Biopsy TissueSmall Amount of Renal Biopsy Tissue

KidneyKidney

Blood PressureBlood Pressure

ResearchResearch


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Clinical parametersClinical parameters VVGG SSGG NNG(pod)G(pod) SSGG//NNG(pod)G(pod) NNG(nonG(non--pod)pod) VVGG//NNG(nonG(non--pod)pod)

Urinary protein excretionUrinary protein excretion r =r = 0.2230.223 0.2320.232 --0.3400.340 0.4260.426 0.4710.471 --0.2120.212

p =p = 0.1640.164 0.1480.148 0.0340.034** 0.0080.008** 0.0030.003** 0.1850.185

Mean blood pressureMean blood pressure r =r = 0.2550.255 0.2920.292 --0.2920.292 0.4960.496 0.3500.350 --0.0390.039

p =p = 0.1170.117 0.0720.072 0.0720.072 0.0020.002** 0.0310.031** 0.8080.808

SerumSerum creatininecreatinine levellevel r =r = 0.1700.170 0.2460.246 0.2080.208 --0.0090.009 0.2300.230 --0.0930.093

p =p = 0.2940.294 0.1290.129 0.1990.199 0.9750.975 0.1560.156 0.5650.565

CreatinineCreatinine clearanceclearance r =r = 0.0710.071 0.0310.031 0.0740.074 --0.2000.200 --0.0630.063 0.1910.191

p =p = 0.0710.071 0.0310.031 0.0740.074 --0.2000.200 --0.0630.063 0.1910.191

MorphometricMorphometric parametersparameters

Correlation between clinical andCorrelation between clinical and morphometricmorphometric

parametersparameters

VG; Glomerular volumes, SG; Glomerular surface areas;VG; Glomerular volumes, SG; Glomerular surface areas; NG (pod);NG (pod); PodocytePodocyte number pernumber per glomerulusglomerulus

SG/NG (pod); Glomerular surface areasSG/NG (pod); Glomerular surface areas coverdcoverd by oneby one podocytepodocyte

NG (nonNG (non--pdopdo); Non); Non--podocytepodocyte cell number percell number per glomerulusglomerulus

VG/NG (NonVG/NG (Non--pod); Glomerular volumes occupied by one nonpod); Glomerular volumes occupied by one non--podocytepodocyte cellcell

(Spearman rank correlation coefficient) *p< 0.05(Spearman rank correlation coefficient) *p< 0.05


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•• Mast cells are bone marrow derived cells, wellMast cells are bone marrow derived cells, wellknown for their roles in anaphylacticknown for their roles in anaphylactic

reactions.reactions.•• Mast cells in the tissues contain large amountsMast cells in the tissues contain large amounts

of the powerful serine proteasesof the powerful serine proteases tryptasetryptase andandchymasechymase..

•• Mast cells were also found to contribute toMast cells were also found to contribute tointerstitial fibrosis in several diseases.interstitial fibrosis in several diseases.

Interstitial mast cell infiltrationInterstitial mast cell infiltration

in primary glomerulonephritisin primary glomerulonephritis


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Chymase TryptaseTryptase

IgA nephropathyIgA nephropathy

(poor prognosis group)(poor prognosis group)

(Inflammatory Res 2007; 56:421-427)


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Chymase

merge

Tryptase

IgA nephropathyIgA nephropathy(poor prognosis group)(poor prognosis group)

It is considered that chymase and tryptase

double positive mast cells may induce thefibrosis and remodeling of various tissues

(JACI 99: 155, 1997).

(Inflammatory Res 2007; 56:421-427)

Li ht i i fi di fLi ht i i fi di f t tt t iti t ll i biiti t ll i bi


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Light microscopic findings ofLight microscopic findings of tryptasetryptase positive mast cells in biopsypositive mast cells in biopsy

specimens stained byspecimens stained by tryptasetryptase and aniline blue in patients with IgAand aniline blue in patients with IgA

nephropathynephropathy

Group IGroup I Group IIGroup II

ArrrowArrrow head:head: tryptasetryptase positive mast cellspositive mast cells


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Number of mast cells per unit area in the wholeNumber of mast cells per unit area in the whole tubulointerstitiumtubulointerstitium (/mm(/mm22))

in patients with IgA nephropathy and minimal changein patients with IgA nephropathy and minimal change nephroticnephrotic syndromesyndrome


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1.1. It appears that the number of mast cellsIt appears that the number of mast cells

per unit area in the whoper unit area in the who tubulointerstitiumtubulointerstitiumare correlated to the degree ofare correlated to the degree of

tubulointerstitialtubulointerstitial fibrosis.fibrosis.

2. The number of mast cells in non2. The number of mast cells in non--fibroticfibroticfields may be one of the factors to predictfields may be one of the factors to predict

the prognosis in patients with IgAthe prognosis in patients with IgA

nephropathy.nephropathy.

NephronNephron 2001; 89: 3912001; 89: 391--397397

SummarySummary

rapidly progressiverapidly progressive


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idiopathicidiopathic

crescenticcrescentic

glomerulonephritisglomerulonephritis

--

bronchial asthmabronchial asthmaseveresevere eosinophiliaeosinophilia

necrotizingnecrotizing granulomagranuloma

++

necrotizingnecrotizing vasculitisvasculitis

in other organin other organ

PP--ANCA (+)ANCA (+)

-- ++

necrotizingnecrotizing granulomagranuloma

in respiratory tractin respiratory tract

CC--ANCA (+)ANCA (+)

p y p gp y p g

nephritic syndromenephritic syndrome

ANCA(+)ANCA(+)

++ --

allergicallergic

granulomatousgranulomatous

vasculitisvasculitis

microscopicmicroscopic

polyarteritispolyarteritis

WegenerWegener’’ss

granulomatosisgranulomatosis

(Arimura Y, 1992)

(MPO)(MPO) (PR 3)(PR 3)


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PP--ANCA (ANCA (IgGIgG)) CC--ANCA (ANCA (IgGIgG))

Initiation of PInitiation of P--ANCA related glomerulonephritisANCA related glomerulonephritis


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Initiation of PInitiation of P ANCA related glomerulonephritisANCA related glomerulonephritis? Unknown stimulation (genetic factors and/or exogenous stimulants,

infection, drugs etc.)

ANCA (anti-neutrophil cytoplasmic antibody) (anti-MPO antibody)

activated

neutrophil

reactive oxygen species (ROS)

protenases

vascular injury

renal injury

RPGNRPGN

focal necrotizing glomerulonephritis

crescentic glomerulonephritis

glomerular endothelial cell

ICAM-1

expression

lymphocyte

infiltration

endothelial cell injury

in situ MPO-anti-MPO

antibody

+

complement activation

inflammatory

cytokines

(IL-8, TNF-αααα)MPO

expression

(+ ) cationic charge

(- ) anionic charge

- binding -

?

secretion

induction


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T t t b d li i l d l bi fi di iTreatment based on clinical and renal biops findings in


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Treatment based on clinical and renal biopsy findings inTreatment based on clinical and renal biopsy findings in

patients with primarypatients with primary glomerulonephritidesglomerulonephritides-- Selection of TreatmentSelection of Treatment --

1) Mild1) Mild hematuriahematuria + Thin basement membrane disease (TBMD) :+ Thin basement membrane disease (TBMD) : no treatmentno treatment

2) Severe2) Severe hematuriahematuria withwith microalbuminuriamicroalbuminuria + IgA nephropathy, non+ IgA nephropathy, non--IgAIgA

proliferativeproliferative GN, TBMD :GN, TBMD : carbazochromecarbazochrome , anti, anti--platelet drugplatelet drug

3)3) HematuriaHematuria and mild to moderate proteinuria + AGN, IgA nephropathy,and mild to moderate proteinuria + AGN, IgA nephropathy,nonnon--IgAIgA proliferativeproliferative GN, MPGN :GN, MPGN : antianti--platelet drug, EPA,platelet drug, EPA, carbazochromecarbazochrome,,

ACE inhibitor, AT1R blocker, corticosteroid (*Tonsillectomy+ACE inhibitor, AT1R blocker, corticosteroid (*Tonsillectomy+steroid pulsesteroid pulse

therapy)therapy)

4) Severe proteinuria and / or4) Severe proteinuria and / or hematuriahematuria + RPGN, MPGN, severe IgA+ RPGN, MPGN, severe IgAnephropathy, MN, MCNS, FGS :nephropathy, MN, MCNS, FGS : corticosteroid (pulse), anticorticosteroid (pulse), anti--platelet drug,platelet drug,

antianti--coagulant, ACE inhibitor, AT1R blocker,coagulant, ACE inhibitor, AT1R blocker, immunosuppresantimmunosuppresant,,

plasma exchangeplasma exchange


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HottaHotta O et al. (Am J KidneyO et al. (Am J Kidney DisDis 38:73638:736--743, 2001)743, 2001)

Tonsillectomy in patients with IgA nephropathyTonsillectomy in patients with IgA nephropathy


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JuntendoJuntendoUniversityUniversity

School of MedicineSchool of MedicineSchool of Medicine

HospitalHospitalHospital


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Division of Nephrology,Division of Nephrology, JuntendoJuntendo UniversityUniversity


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Division of Nephrology,Division of Nephrology, JuntendoJuntendo UniversityUniversity


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Terminology of affectedTerminology of affected glomeruliglomeruli


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diffusediffuse

focalfocal

globalglobal

segmentalsegmental

Terminology of affectedgy glomerulig


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EharaEhara T et al. Contribution of mast cells to theT et al. Contribution of mast cells to thetubulointerstitialtubulointerstitial lesions in IgA nephritis.lesions in IgA nephritis.

KidneyKidney IntInt 1998;54:16751998;54:1675--1683.1683.

HiromuraHiromura K et al.K et al. TubulointerstitialTubulointerstitial mast cellmast cellinfiltration in glomerulonephritis.infiltration in glomerulonephritis.

Am J KidneyAm J Kidney DisDis 1998;32:5931998;32:593--599.599.

Kondo S et al. Role of mast cellKondo S et al. Role of mast cell tryptasetryptase in renal interstitialin renal interstitialfibrosis.fibrosis.

J Am SocJ Am Soc NephrolNephrol 2001;12:16682001;12:1668--1676.1676.

Mast cell infiltration andMast cell infiltration and TubulointerstitialTubulointerstitial lesionlesion

L fL f P d tP d t d Gl l l id Gl l l i


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Loss ofLoss of PodocytePodocyte and Glomerulosclerosisand Glomerulosclerosis

((KritzKritz W et al.)W et al.)


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Cellular crescentCellular crescent FibrocellularFibrocellular crescentcrescent Fibrous crescentFibrous crescent

progressionprogressioncrescentcrescent

glomerulusglomerulus


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Protocol of tonsillectomy and steroid therapyProtocol of tonsillectomy and steroid therapy

1. Prednisolone (PSL) 0.5mg/kg alternately, oral

administration (per os) for 2months

2. Methylprednisolone 500mg, DIV for 3 days(2nd)

3. Methylprednisolone 500mg,DIV for 3 days(1st)

more than 2 weeks after the tonsillectomy

4. PSL 0.5mg/kg alternately, per os for 2months

5. Methylprednisolone 500mg, DIV for 3 days(3rd)6. Tonsillectomy

7. PSL 0.5mg/kg alternately, per os for 2months

8. PSL 0.25mg/kg alternately, per os for 1 week

9. PSL 0.125mg/kg alternately, per os for 1 week

10.Completion

Division of Nephrology, Division of Nephrology, Juntendo Juntendo UniversityUniversity

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4th May Session 2 (a) Yasuhiko Tomino