Histopathology of AKI Peter Boor pboor@ukaachen.de Pathology & - - PowerPoint PPT Presentation

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Histopathology of AKI Peter Boor pboor@ukaachen.de Pathology & - - PowerPoint PPT Presentation

Apr 11, 2023 266 likes •861 views

3rd International Symposium on Functional Renal Imaging, 17 th October 2019 Histopathology of AKI Peter Boor pboor@ukaachen.de Pathology & Nephrology RWTH Aachen, Germany Funding: Classification of acute kidney injury (AKI)

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Peter Boor

pboor@ukaachen.de

Pathology & Nephrology RWTH Aachen, Germany

Histopathology of AKI

Funding: 3rd International Symposium on Functional Renal Imaging, 17th October 2019

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Risk Injury Failure Loss ESRD

1,5-2 x

  • r

≥0,3 mg/dl End Stage Renal Disease

Serum-Creatinin Urin output

< 0,3ml/kg/h

  • ver 24 h or

Anuria over 12 h < 0,5ml/kg/h over 6 h >3 x

  • r 4mg/dl

(acute increase 0.5 mg/dl)

High sensitivity High specificity

Persistent Renal Failure > 4 Weeks

Bellomo et al, Crit Care 2004

< 0,5ml/kg/h over12 h 2-3 x

Stage 1 2 3

Classification of acute kidney injury (AKI)

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Hoste et al, Crit Care 2006

AKI is common particularly on intensive wards

retrospective analyses (USA, 7 intensive wards, n=5.383)

No AKI (33%) Stage I (12%) Stage II (27%) Stage III (28%)

maximal reached RIFLE-stage

Cumulative survival

Days in hospital after AKI

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Causes of acute kidney injury (AKI)

Modified from Floege/Feehally, Comprehensive clinical nephrology

45%

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AKI in renal biopsies

Modified from Floege/Feehally, Comprehensive clinical nephrology

45%

Biopsied Biopsied Biopsied Not-biopsied Not-biopsied Biopsied

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Case 1: Clinical presentation: unclear AKI, Voltaren medication (NSAID), contact with murine feces

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Case 2: Living donor transplant 1 week ago. Crea increase from 2,1 to 3 in 2 days. Rejection?

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Acute tubular injury & necrosis

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Case 3: Time 0 biopsy, deceased donor

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Acute tubular injury Very little chronic injury, no other pathology

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Case 4: Transplant biopsy after reperfusion (no other data provided)

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Acute tubular injury Very little chronic injury, no other pathology

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Case 5: Unclear renal insufficiency No medication

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Acute interstitial nephritis With mainly acute tubular injury

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Case 6: Unclear renal insuficiency Crea 5,9mg/dl, GFR ca. 10.

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Lymphocytic interstitial Nephritis With acute tubular injury

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Ischemia-reperfusion injury in mice (warm, 35 min, females, time-point 6 hrs)

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Ischemia-reperfusion injury in mice (warm, 35 min, females, time-point 24 hrs)

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Nephrotoxins:

a) exogenous:

  • iodinated contrast
  • aminoglycosides
  • cisplatin

b) endogenous

  • hemolysis
  • rhabdomyolysis
  • myeloma
  • intratubular crystals

Etiology of acute kidney injury (AKI)

Acute kidney injury

prerenal intrinsic postrenal

  • Hypovolemia
  • Decreased cardiac
  • utput/Congestive

heart failure

  • Reduced effective

blood volume, liver cirrhosis

  • Impaired renal

autoregulation

  • NSAID, ACE-Inhib.
  • Cyclosporine
  • Bladder outlet
  • bstruction
  • Bilateral pelvouretheral
  • bstruction
  • Unilateral obstruction
  • f a solitary

functioning kidney glomerular

  • Acute GN

tubular vascular

  • Vasculitis
  • HUS/TTP

Ischemia Sepsis/Infection

Modified from Harrison‘s Principles

  • f internal medecine, 20th edition
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Conventional animal models for AKI

Acute kidney injury

Prerenal intrinsic postrenal Ischemia/Reperfusion Unilateral Ureter

  • bstruction ( UUO)

Tubular- Endogenous toxins: a) Pigmentnephropathy

  • Glycerol model (rhabdomylosis)
  • Infusion of myoglobin

b) Warfarin-nephropathy c) Sepsis induced AKI ( also prerenal)

  • LPS Modell
  • Cecal ligation and punction ( CLP-

model) Tubular-Exogenous toxins: a) Cisplatin induced AKI b) Folic acid induced AKI c) Aristolochic acid induced AKI d) Adriamycin induced AKI e) Contrast induced AKI f) Organic mercury induced AKI Glomerular: a)Puromycin aminoglycoside (PAN) model b) Adriamycin induced AKI ( FSGS) c) Nephrotoxic nephritis (NTN) Vascular: a) STX2 Model b) Anti-GBM Model

most commonly used

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Clinical phases of AKI

Rosner & Okusa CJASN 2006; Sutton & Fisher & Molitoris KI 2002

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Clinical phases of AKI

Prerenal phase Initiation Extension Maintainance Repair

Loss of polarity, loss of brush border Necrosis and apoptosis Luminal obstruction with scattered cells Cell Surviving Migration and dedifferentiation of viable cells Repolarisation, differentiation

Reconstitution

Healthy tubular cells

modified from Bonventre et al JCI 2011

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Common problems of models for AKI humans

rodents

comorbidities mechanical ventilation cardio- pulmonar- arrest no tissue available medications different biology same diet same environment

  • ther

comorbidities than humans young age, responsive vasculature

  • lder age,

senescent epithelial cells

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Challenges and solutions in translation

McCafferty et al 2014

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Combine clinical & preclinical research - Role of MIF in AKI

Stoppe…Boor, Sci Transl Med 2018

Cohort studies in patients after cardiac surgery

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Combine approaches - role of MIF in AKI & tubular injury

Stoppe…Boor, Sci Transl Med 2018

Clinical studies

patients after cardiac surgery

Preclinical studies

Different animal AKI models & interventions & in vitro mechanistic studies

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Combine approaches - role of MIF in AKI & tubular injury

Stoppe…Boor, Sci Transl Med 2018

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Kidney autofluorescence (tubular cells) Peritubular capillaries (2000 kDa dextrane-FITC, 50 µl of 5mg/ml) ) Evans blue (1µl/g BW of 1mg/ml)

sham Postrenal AKI (UUO d5) Other processes in AKI – microvascular dysfunction (in vivo imaging)

Babickova…Boor, Kidney Int 2017

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Pathological process-specific kidney imaging

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Approach to molecular imaging in kidneys (renal fibrosis)

Target validation Specificity Applicability

Sun…Boor, Sci Transl Med 2019

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Elastin is up-regulated in models of renal fibrosis (target validation)

Adenine nephropathy Fibrotic Healthy

P e riv a s c u la r a re a E la stin area (% )

H e a lth y U U O

0 .0 0 .2 0 .4 0 .6 0 .8

 

C o rte x E la s tin a re a (% )

H e a l t h y U U O

0 .0 0 0 .0 5 0 .1 0 0 .1 5 0 .2 0

M e d u lla E la s tin a re a (% )

H e a l t h y U U O

0 .0 0 .2 0 .4 0 .6 0 .8 1 .0

  

Sun…Boor, Sci Transl Med 2019

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Confirmation in other animal models

Rat: UUO, 5/6 Nx, chronic anti-Thy1.1 Nephritis, adenine nephropathy Mouse: UUO, I/R injury, NTN, Alport mice (Col4a3-/-), 5/6 Nx, Folic acid nephropathy Methods: IHC, IF, WB, qRT-PCR, electron microscopy Sun…Boor, Sci Transl Med 2019

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Elastin is up-regulated in patients with renal fibrosis

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Elastin expression in human kidneys

Sun…Boor, Sci Transl Med 2019

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Elastin-specific magnetic resonance contrast agent (ESMA)

Makowski et al. Nat Med 2011

153Gd-DTPA linked to D-amino acid D-phenylalanine

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ESMA MRI in adenine nephropathy

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ESMA MRI in adenine nephropathy

Sun…Boor, Sci Transl Med 2019

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Specificity

Elastin expression Renal Gd-content ex vivo competition in vivo competition

(laser ablation) inductively coupled plasma mass spectrometry – LA-ICP-MS Sun…Boor, Sci Transl Med 2019

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ESMA binds to human kidney ex vivo

Fibrosis Healthy Fibrosis Healthy

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Renal Fibrosis

Baues…Boor et al., Adv Drug Deliv Res 2018

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ESMA pharmacokinetics & longitudinal measures

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ESMA imaging monitors anti-fibrotic therapy efficacy

Vehicle CRID3

Control (H2O) Imatinib

CRID3 in Adenine nephropathy Imatinib in I/R

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ESMA imaging - just another surrogate for GFR?

Serum creatinine Serum urea

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Serum creatinine Serum urea Elastin IF Elastin WB Collagen 3

ESMA imaging in reversible adenine nephropathy

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Elastin imaging identifies residual renal fibrosis not detectable using routine kidney function measurement

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Collagen imaging in renal fibrosis

Baues…Boor, Kidney Int 2019

fibrotic healthy

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Collagen imaging in renal fibrosis

Baues…Boor, Kidney Int 2019

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Will pathology be needed with all the non-invasive diagnostic??

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Yes – perhaps more than ever… Digital & Computational Pathology

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Digital Pathology – augmented by deep learning

Boor Nat Rev Nephrol 2019

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Digital Pathology – augmented by deep learning

Kather…Boor et al., Nat Med 2019

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Acute Kidney Injury

  • common & relevant disease
  • pathophysiology mainly from animal models (relevance?)
  • limited data from human kidney tissue
  • hallmark - tubular injury (variable degree)
  • various other processes involved (microvascular dysfunction…)
  • non-invasive & disease process-specific biomarkers needed

pboor@ukaachen.de Conclusions