Novel Imaging Technologies In Acute and Chronic Kidney Injury Models - - PowerPoint PPT Presentation

Novel Imaging Technologies In Acute and Chronic Kidney Injury Models

Rachel Harwood PhD Student Paediatric Surgery Registrar

40% children on PICU 15% of inpatients Long term morbidity £1.44-£1.45 Billion, per year

Models of injury

• Nephrotoxicity models
• Cisplatin
• Adriamycin
• Folic Acid
• Warfarin
• Gentamycin
• Surgical models
• Ischaemia Reperfusion Injury
• 5/6 nephrectomy
• Ureteric Obstruction
• Systemic models
• Sepsis
• Diabetic nephropathy
• Rhabdomyolysis (Glycerol)

Ischaemia Reperfusion Injury

Monitoring Disease Progression

Imaging Serum Histology Urine

NAG α-GST β2-MG ɑ1-MG RBP Cys-C MicroAlb KIM-1 NGAL IL-18 FABP Creatinine BUN Cys-C Ultrasound DMSA MAG3 ? MRI TIS H&E PicroRed Masson’s

Transcutaneous FITC- Sinistrin Clearance Multi-spectral

• ptoacoustic

tomography (MSOT) Clearance of IRDye800 CW

FIT FITC-Si Sinistrin Cle Clear arance ance

RIFLE classification of GFR reduction

Percentage GFR loss

Day 0 Day 1 Day 3 Day 7 Day 14 100 150 200

25 minutes 27.5 minutes 30 minutes Sham

Risk Injury Failure

*** *** ** GFR of all surviving animals

GFR (µl/min/100g)

Day 0 Day 1 Day 3 Day 7 Day 14 500 1000 1500 2000 2500

25 minutes 27.5 minutes 30 minutes Sham

*** * ***

Bilateral Ischaemia Reperfusion Injury

Correlation between anaesthetic duration, pre-clamping anaestheic time and day 1 GFR

Day 1 GFR (µl/min/100g) Duration (Minutes)

200 400 600 800 50 100 150

Total anaesthetic time 25 minute clamp 27.5 minute clamp 30 minute clamp Pre-clamping anaesthetic time r2 - 0.50 p 0.0034 r2 - 0.34 p 0.0219

Failure

Day 1 GFR (µl/min/100g) Duration (Minutes)

200 400 600 800 10 20 30 40 50

Clamping time Post-clamping anaesthetic time 25 minute clamp 27.5 minute clamp 30 minute clamp

Correlation between clamping time, post clamping anaesthetic time and day 1 GFR

r2 - 0.13 p 0.1522 r2 0.00 p 0.8559

Failure

Day 14 after Bilateral IRI

Cortical collagen deposition

PSR Score

Right Kidney Left Kidney Both Kidneys 2 4 6

25 minutes 27.5 minutes 30 minutes Sham

0.04 Relationship between acute injury and development

• f cortical collagen deposition

GFR (µl/min/100g) Combined collagen deposition

500 1000 1500 2000 2 4 6 8

r2 - 0.69 p < 0.0001 Serum Creatinine

Creatinine (mg/dL)

2 5 m i n u t e s 2 7 . 5 m i n u t e s 3 m i n u t e s S h a m 0.0 0.5 1.0 1.5

0.045 Serum Urea

Urea (mg/dL)

2 5 m i n u t e s 2 7 . 5 m i n u t e s 3 m i n u t e s S h a m 20 40 60 80 100

Serum Cystatin C

Cystatin C (mg/l)

2 5 m i n u t e s 2 7 . 5 m i n u t e s 3 m i n u t e s S h a m 0.0 0.5 1.0 1.5

MS MSOT

Unilateral Ischaemia Reperfusion Injury

IRI Chronic Kidney Disease Model

Change in GFR over time

Day after R-IRI GFR (µl/min/100g)

10 20 30 40 50 500 1000 1500 2000

Refined Unilateral Ischaemia Reperfusion Injury

1 3 9 13

• 100

100 200 300 400 500

Change in tmax after unilateral IRI

Day after R-IRI tmax Injured Kidney Uninjured Kidney ** * * p < 0.05 ** p < 0.01

Creatinine

Subject Creatinine (mg/dL)

1 2 3 4 5 0.0 0.5 1.0 1.5

Cystatin C

Subject Cystatin C (mg/l)

1 2 3 4 5 1 2 3

Urea

Subject Urea (mg/dL)

1 2 3 4 5 50 100 150 200 250

PSR score

Subject PSR Score

1 2 3 4 5 1 2 3 4

Refined Unilateral Ischaemia Reperfusion Injury

Comparison of PSR score and GFR in CKD models

PSR score GFR (µl/min/100g)

1 2 3 4 5 500 1000 1500 2000

r2 - 0.93 p 0.0004

Take Home Messages

• The use of non-invasive monitoring can
• enable better refinement of a kidney injury model
• reduce the numbers of subjects required for efficacy studies
• Has the potential to improve knowledge about mechanisms of injury
• The future
• Efficacy studies
• Alternative dyes for MSOT
• ? Translation to humans

Thanks to

Prof P Murray Prof S Kenny Dr B Wilm Dr J Sharkey Dr L Scarfe Dr A Taylor