Tanja Herrler, MD Department of Surgery, University of Munich, … · 2016. 8. 9. · 15 STUDY...

Tanja Herrler, MDDepartment of Surgery, University of Munich, Germany

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University of Munich | Tanja Herrler

Tanja HerrlerExperimental Medicine – TransplantationDepartment of Surgery, Campus Großhadern, University of Munich

THE ROLE OF NUCLEAR MEDICINE IN RENAL TRANSPLANTATIONEnhancing the identification of renoprotective treatment modalitiesfor improved renal function following kidney transplantation

Campus GroßhadernChirurgische Klinik

Tanja Herrler | University of MunichISCORN 2010 Symposium, Mikulov 3

GRAFT SURVIVAL (%)

Collaborative Transplant Study 2007Transplantation Immunology Department, University of Heidelberg, GERMANY(400 transplant centers in 45 countries)

All transplants 1985-2007


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CHRONIC ALLOGRAFT NEPHROPATHYMajor cause of dysfunction and loss of the transplant kidney

Pascual et al., N Engl J Med 2002Tanja Herrler | University of MunichISCORN 2010 Symposium, Mikulov


Tanja Herrler | Experimentelle Forschung Chirurgie 5

KIDNEY REGENERATION

Renaltubules

Peritubularcapillaries

Interstitium

Resident renalstem cells

MSC

CEC

EPC

VEGFSDF

Peritubularendothelial cells Tubular

cells

ProliferationDifferentiation

DedifferentiationSurviving cells

KidneyinjuryMSC

Adapted from Haller, Internist 2007 ISCORN 2010 Symposium, Mikulov


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DETERMINATION OF KIDNEY FUNCTION IN A MURINE MODEL OF RENAL ISCHEMIA-REPERFUSION INJURY

K+bilateral renal

Ischemia-reperfusion

ClassicVariableInsufficient

Creatinine ProteinuriaXX XXO'Donnell et al., Transplantation 2002

Tanja Herrler | University of MunichISCORN 2010 Symposium, Mikulov

99mTechnetium-MAG-3Mercapto-acetyl-tri-glycine+ tubular excretion+ longitudinal studies+ long-term follow-up+ short half life+ unilateral kidney injury

NewSensitiveSpecific Proximal

tubuleDistaltubule

Loop of Henle

Glomerulus

Collecting ductRoberts et al., Am J Physiol Renal Physiol 2007

XX


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99mTc-MAG3 IMAGING

Peak @ 10 min

Whole body scintigraphy using a triple-headed gamma camera, each detector equipped with a LEHR collimatorstandardized dose of ~3.7x107 Bq i.v. per mouse and simultanous acquisition in a dynamic planar techniqueCollection of 1 frame per 5 sec, total scan time 10 minimage acquisition magnification set to 4 times Image analysis using Hermes dynamic analysis software V4.1 (Hermes Medical Solution, Stockholm, Sweden)

f(x) = (right kidney ROI – background ROI) : (whole body ROI – injection ROI) x 100 = %ID Tanja Herrler | University of MunichISCORN 2010 Symposium, Mikulov


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PROBLEM No. 1Optimal ischemia time in murine model of ischemia-reperfusion injury?

35 min35 min 40 min40 min 45 min45 min HealthyHealthy



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STUDY DESIGN

Day Day --4 4

99m99mTcTc--MAG3 imagingMAG3 imaging 99m99mTcTc--MAG3 imagingMAG3 imagingLaser doppler perfusionLaser doppler perfusionHistologyHistologyImmunohistochemistry Immunohistochemistry

Renal I/R unilateral 45 minRenal I/R unilateral 45 minBalb/C nu/nuBalb/C nu/nu

Day 0Day 0 Day 2Day 2 Day 18Day 18

99m99mTcTc--MAG3 imagingMAG3 imaging

Murine model of ischemia-reperfusion injury

Day 1Day 1

101066 hEPC/hEPC/hMSC i.v.hMSC i.v.



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STEM/ PROGENITOR CELL THERAPY IN RENAL ISCHEMIA-REPERFUSION INJURYHistology & ScintigraphyHealthy 45 min ischemia 45 min ischemia + ECFC


45 min ischemia + MSC


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PATHOPHYSIOLOGY OF POSTISCHEMIC INFLAMMATORY EDEMAA vicious circle



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ANATOMY OF THE KIDNEYThe tight fibrous kidney capsule has little ability to accomodate volume shift


Netter‘s Atlas of Anatomy


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INTRACAPSULAR PRESSURE IN RENAL ISCHEMIA-REPERFUSION INJURYThe intrinsic renal compartment syndrome

* p<0.001 vs. healthy, p<0.05 vs. 35 min** p<0.05 vs. healthy

*

** *

** **

**

Herrler et al., Transplantation 2010


45 m

in is

chem

ia 6h reperfusion 12h reperfusion 24h reperfusion 48h reperfusion


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SITE AND EFFECT OF SURGICAL DECOMPRESSION THERAPYIN THE ISCHEMIC KIDNEY



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STUDY DESIGN

Day Day --4 4

99m99mTcTc--MAG3 imagingMAG3 imaging 99m99mTcTc--MAG3 imagingMAG3 imagingLaser doppler perfusionLaser doppler perfusionHistologyHistologyImmunohistochemistry Immunohistochemistry

Renal I/R unilateral 45 minRenal I/R unilateral 45 minBalb/C wtBalb/C wtControl vs.Control vs.Incision of kidney capsuleIncision of kidney capsule

Day 0Day 0 Day 2Day 2 Day 18Day 18

99m99mTcTc--MAG3 imagingMAG3 imaging



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45 min ischemiaCo

ntrol

Micro

-caps

ulotom

yMICRO-CAPSULOTOMY PRESERVES KIDNEY FUNCTION IN RENAL ISCHEMIA-REPERFUSION INJURY (BALB/C WT MICE)




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TUBULAR EXCRETION IN RENAL ISCHEMIA-REPERFUSION INJURYRenoprotective effects of surgical decompression therapy

* p<0.001 vs. pre** p<0.05 vs. control

**

* p<0.001 vs. pre* * p<0.01 vs. control

**

* *




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LASER DOPPLER-ASSESSED KIDNEY PERFUSION Surgical decompression therapy preserves renal blood flow

HealthyHealthy ControlControl

* p<0.005 vs. healthy** p<0.05 vs. control, n.s. vs. healthy

**

*




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ANALYIS OF KIDNEY SIZE AND WEIGHTSurgical decompression therapy prevents atrophy

* p<0.05 vs. healthy* * p<0.01 vs. control, n.s. vs. healthy

**

* healthy

R L

I/R control

healthy

healthy

healthyI/R

therapy




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HISTOLOGICAL ANALYSIS (H&E)Surgical decompression preserves integritiy of renal structures

control healthytherapy45 min renal ischemia - 18days reperfusion




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TUBULAR FUNCTION FOLLOWING RENAL ISCHEMIA-REPERFUSION INJURYRenoprotective effects of combination therapy

(n=4)

(n=5)

* p<0.01 vs. control

**

* p<0.01 vs. control



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LASER DOPPLER-ASSESSED KIDNEY PERFUSION Surgical decompression therapy preserves renal blood flow

* p<0.001 vs. control** p< 0.05 vs. control

**

* *



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HISTOLOGICAL ANALYSIS (H&E)Preservation of the integritiy of renal structures using combination therapy

controlhealthy ECFC alone

45min renal ischemia - 18days reperfusion

decompressionalone

ECFC+ decompression

* p<0.01 vs. control** n.s. vs. control

**

* *

Tubular injury scorecellular necrosisloss of brush bordercast formationvacuolization,tubule dilation 0: none1: 10%2: 11 to 25%3: 26 to 45%4: 46 to 75%5: >76%.



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IMMUNOSUPPRESSIVE AGENTS IN KIDNEY TRANSPLANTATIONTherapy evaluation using 99mTc-MAG3 imaging


n.s.

P<0.01

P<0.01

P<0.05

P<0.01 P<0.05

n.s.

Control CsA DEX SRL Control CsA DEX SRL

Control CsA DEX SRL Control CsA DEX SRL

Rena

l func

tion p

eak (

% ba

selin

e)

Rena

l func

tion p

eak (

% ba

selin

e)Tu

bular

excre

tion r

ate (%

base

line)

Tubu

lar ex

cretio

n rate

(% ba

selin

e)

Contralateral healthy kidney – 48h reperfusion

Contralateral healthy kidney – 48h reperfusion

45 min ischemia – 48 h reperfusion

45 min ischemia – 48h reperfusion

CsA cyclosporine ADEX dexamthasoneSRL sirolimus/ rapamycin


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99mTc-MAG3 IMAGING IN PRECLINICAL RESEARCH…Conclusion and perspectives− represents reliable endpoint for the determination of early and long-term renal function following renal ischemia-reperfusion injury− enabled us to establish micro-capsulotomy for enhanced functional recovery− demonstrated that decompressive treatment is required to exploit additional benefits of a cell-based therapy for kidney recovery after ischemia-reperfusion injury− provides more insights into functional effects of immunosuppressive agents following renal ischemia-reperfusion injury for optimized clinical application.− contributes to the identification of effective treatment modalities in renal ischemia-reperfusion injury for improved function and survival of the renal allograft.− facilitates pre-clinical therapy evaluation

Next steps: − Verification in preclinical model of kidney transplantation− Translation into clinical application



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Walter Brendel Center for Experimental Medicine, University of MunichU. Pohl, E. Thein

Experimental Neurosurgery, University of MunichN. Terpollili, S. Feiler

Department of Internal Medicine - Nephrology, University of MunichM. Fischereder, H.J. AndersDepartment of Nuclear Medicine, University of MunichP. Bartenstein, M. Hacker, S. NowakDepartment of Surgery, Campus Großhadern, University of MunichK.W. Jauch, M. Guba, M. Rentsch, J. Andrassy, S. Huber, A. Meyer,A. Tischer, T. Herrler

This work was supported by:Else Kröner-Fresenius-Stiftung and Friedrich-Baur-Stiftung.

PARTNERS



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KIDNEY ANATOMY

Interlobar vessels

Arcuate vessels

GlomerulusBowman‘s capsule

Efferent arteriole

Proximal tubuleCortical capillary network

Collecting tubule

Henle‘s loop


Tanja Herrler, MD Department of Surgery, University of Munich, … · 2016. 8. 9. · 15 STUDY...

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