WARMING UP TO ISCHEMIA

Dipen J. Parekh

Professor and Chairman,

Department of Urology,

Victor A Politano Endowed Chair in Urology,

University of Miami Miller School of Medicine

WHAT ARE THE GOALS OF A PARTIAL

NEPHRECTOMY FOR RCC ?

• Primary – Oncologic Efficacy

• Secondary

• Preserve Renal Function

• Reduce Perioperative morbidity

• Cosmesis

Why is renal function important ?

RENAL FUNCTION • 25% with localized RCC undergoing surgery

have pre-existing CKD even with normal serum

creatinine

• 20% of patients undergoing PN will manifest

CKD-III within 5 years of surgery

• 50-60% of patients undergoing will develop

CKD-III within 5 years of surgery

Decreasing GFR correlated with risk of

death, CVS events, and hospitalization

PREVENTIVE MEASURES

• Pre-operative evaluation

• Identify proteinuria, hypertension,

hyperlipidemia and reduced eGFR

• Early referral to a Nephrologist has been

shown to reduce mortality in a cohort of

diabetic patients with CKD

• Use of renoprotective agents has not shown any

benefit

1997-2000

n= 39031 pts w/ DM and CKD III/IV

Mortality risk to # visits

Tseng CL, et al. Arch Int Med 2008; 165:55-62

Survival benefit of nephrological care

Hazard

Ratio

95%CI

2

visits

3

visits

4

visits

0.80

0.68

0.45

0.67-

0.97

0.55-

0.86

0.32-

0.63

THE BEST WAY TO PRESERVE RENAL

FUNCTION

Nephron sparing surgery

BASELINE RENAL FUNCTION

• Quality of baseline renal parenchyma sets the ceiling

for post-operative recovery

• Major predictor of post-operative acute renal failure

(ARF) and ESRD after PN

• Pre-operative eGFR is an independent predictor of:

• Significant decrease in eGFR in solitary kidneys

• Differential contribution of the operated organ in the

presence of bilateral functioning kidneys

RENAL PARENCHYMAL VOLUME

AFTER PN• Percentage of preserved parenchyma is a

significant and independent predictor of ultimate

global renal function and function of the affected

kidney

• Strong correlation - volume of parenchyma

removed, surgical complexity and WIT

• 5% increase in the amount of kidney preserved

correlates with 17% reduction in risk of post-

operative de novo CKD-IV

Case 1

63 year female

Serum creatinine 0.7

No co-morbidities

Warm Ischemia Time

20 minutes

Case 2

70 year female

Serum

creatinine 1.2

H/O DM, HTN,

well controlled

Warm Ischemia Time

32 minutes

Warm Ischemia Time 20 min

versus 32 min

Important ?

RENAL ISCHEMIA

• How reliable is the evidence that limited

ischemia is unsafe ?

• “ It ain’t what you don’t know that gets you

into trouble, It’s what you know for sure

that just ain’t so” – Mark Twain

With the information just provided, should

we have accepted it as gospel ?

• 362 pts undergoing PN in solitary kidneys from

Mayo Clinic and Cleveland Clinic from 1990-

2008

• WIT as a continuous variable found to be an

independent predictor of adverse renal

functional outcomes – Therefore every single

minute of WIT adds to the damage and counts !

• WIT of 25 min proposed as a new safe cut off

Eur Urol , 2010

• 362 pts undergoing PN in solitary kidneys from

Mayo Clinic and Cleveland Clinic from 1990-

2008

• WIT as a continuous variable did not significantly

associate with long term renal function after

adjusting for quality and quantity of remnant

renal parenchyma

• Every single minute does not count !

Urology , 2012

• From 1980-2009, 660 pts undergoing PN in a

solitary kidneys from 4 institutions

• Ischemia Time was NOT an independent

predictor of ultimate renal function after PN

• Quantity and Quality of remnant renal

parenchyma was more important…….

J Urol , Feb 2011

The flaw of retrospective studies,

selection and investigator biases and

not knowing what we don’t know

WHAT DO ALL THE PREVIOUS ARTICLES

PROVE ?

Sanity is not statistical

George Orwell, 1948

Eur Urol 2015

CONSENSUS

• “Consensus: “The process of abandoning

all beliefs, principles, values, and policies

in search of something in which no one

believes, but to which no one objects; the

process of avoiding the very issues that

have to be solved, merely because you

cannot get agreement on the way ahead.

What great cause would have been fought

and won under the banner: ‘I stand for

consensus?” Margaret Thatcher

Eur Urol 2015

PRESENT KNOWLEDGE OF

ISCHEMIA IN THE HUMAN KIDNEY

• Current teaching suggests that every minute of

renal ischemia increases risk of renal functional

impairment

– Data from: animal, renal transplant ,

retrospective human studies

• Novel biomarkers implicated in Acute Kidney

Injury from diverse causes

• The role of biomarkers in the setting of partial

nephrectomy is undefined

GOALS• In the setting of partial nephrectomy

• To determine if duration of ischemia time

impacts renal function

• To evaluate the role of novel biomarkers in

predicting renal functional changes

– Functional Biomarkers

– Structural Biomarkers

– Electron Microscopy

– Immunofluorescence

Trial Design

• 40 patients prospectively enrolled

– February 2009 – October 2010

– Informed Consent

• Open partial nephrectomy

– Single surgeon

– Uninvolved contralateral kidney

– No pre-existing end stage renal disease

TRIAL DESIGN

Pre-op

BIOPSY SCHEMA

Unique attributes

• Surgeon blinded to all clinical,biomarker

and structural data till end of the study

• Pathologist and Nephrologist blinded to

clinical data till end of study

• Biomarkers evaluated at a lab blinded to

all other data

Results

• Mean age – 55 years (range 28-84)

• Median tumor size – 4.1 cm (range 2.0 - 8.0)

• Warm ischemia in 27 and cold ischemia in 13

patients

• Mean duration of ischemia

– Warm - 32.3 minutes (range 15 - 53)

– Cold - 48.0 minutes (range 30 - 61)

80% (33/40) of patients had ischemia > 30

minutes

BIOMARKERS

FUNCTIONAL

• SERUM

– Creatinine

– Cystatin C

STRUCTURAL

• SERUM

• URINE

- NGAL Neutrophil Gelatinase Associated

Lipocalin

- NGAL

- NAG N-Acetyl-Beta-D Glucosaminidase

- L-FABP Liver Fatty Acid Binding Protein

- KIM-1 Kidney Injury Molecule-1

- IL-18 Interleukin-18 -- Inflammation

WARM

COLD

RECOVERY TIME (hours)

Pre 2 24 48 72 96

mg/d

l

0.0

0.5

1.0

1.5

2.0Serum Creatinine

0.790.84

0.971.08

FUNCTIONAL BIOMARKERS

WARM

COLD

Pre 2 24

ng

/ml

0.0

0.5

1.0

1.5

2.0

Serum Cystatin C

p<0.0001 at 24 h

p = 0.15 at 72 h

p=0.94 at 24h

Transient increase in

serum Creatinine

No changes in

serum Cystatin C

Serum Cystatin C

Recovery Time (hours)

ng

/ml

Pre 2 240.0

0.5

1.0

1.5

p=0.17p=0.64

Serum Creatinine

Recovery Time (hours)

mg

/dl

Pre 2 24 48 720.0

0.5

1.0

1.5

2.0

2.5

p<0.0001p=0.182

FUNCTIONAL BIOMARKERS

b=0.003

p=0.49

b=-0.004

p=0.27

X-axis = Ischemia time

Y-axis = 24h to baseline ratio

e

NO CORRELATION WITH DURATION OF ISCHEMIA

STRUCTURAL BIOMARKERS

X-axis = Ischemia time, Y-axis = Peak to baseline biomarker ratio

NO CORRELATION WITH DURATION OF ISCHEMIA

b=-7.79

p=0.31

How much of an insult does the

normal human renal parenchyma

sustain under clamp induced

ischemic conditions?

ELECTRON MICROSCOPY

AND

ULTRASTRUCTURE

IN ANIMAL MODELS . . .

Venkatachalam MA , Kidney Int 1978

Molitoris et al. J. Clin. Invest. 106:233,1989

5 MINUTES

ISCHEMIA

15 MINUTES

ISCHEMIA

30 MINUTES

ISCHEMIA

30’ ISCHEMIA 60’ ISCHEMIA

15’ ISCHEMIA

RABBIT ISCHEMIA IN VIVO

NORMOXIC

Composite Scale of Injury on EM> 300 biopsies, > 2000 EMs reviewed by subject matter authority

Stage Description

0 Absolutely pristine

1

Minimal BBM discontinuity, apical membrane blebbing without shedding.

Mild mitochondrial swelling limited to DTs. Mild occasional IC expansion.

Occasional pale cells noted.

2

Moderate mitochondrial swelling in PTs, moderate to severe swelling of

DTs. Mitochondrial condensation. BBM fragmentation, thinning or

discontinuities. Occasional lumenal blebs.

3

BBM thinning, fragmentation. Lumenal bleb casts. Uniform higher

amplitude mitochondrial swelling in PTs and DTs, but with preservation of

cristae and overall architecture. Changes present in any tubule, but not

present in all.

4 Stage 3 changes seen in every tubule.

5Presence of necrotic cells with large amplitude MPT type mitochondrial

swelling, plasma membrane disruption, loss of cytosolic content.

61 MIN OF COLD

ISCHEMIA

REPERFUSION

AT 5 MIN

NORMAL PROXIMAL

TUBULE

a cb

d fe

GLOMERULAR ULTRASTRUCTURE

The degree of insult at the ultrastructural level

was relatively mild and reversible in all patients

EM staging

Pre = Baseline, End = Maximum duration of ischemia, Post = Reperfusion at 5 mins

Pre to

End

p <

0.0001

Pre to

Post

p <

0.0001

End to

Post

P =

0.0001

X -axis = Ischemia time , Y-axis = EM score difference

EM INJURY SCORE

NO CORRELATION WITH DURATION OF ISCHEMIA

Pre-Clamp

Ischemia Time (min)

EM

Sco

re

20 40 60

0

1

2

3

4

No changes

IntegrinActin pTyr

MINIMAL

changes

Baseline

31 minutes of warm ischemia

Reperfusion at 5 minutes

IN A PROSPECTIVE TRIAL

Functional Biomarkers

+

Structural Biomarkers

+

Electron Microscopy

+

Immunofluorescence

No correlation with the

duration of ischemia

time

Minimal structural and

functional reversible

changes

=

CORRELATIVE ANALYSIS

ACUTE KIDNEY INJURY

Loef B G et al. JASN 2005;16:195-200

RIFLE CLASSIFICATION (Risk, Injury, Failure, Loss and End-Stage kidney

Disease)

AKIN CLASSIFICATION – Stage 1-3

SIGNIFICANCE OF STAGE 1 AKIN AND EARLY STAGES OF RIFLE IS UNKNOWN

AKI 20% DIALYSIS 3%

SIGNIFICANT AKI / DIALYSIS IN CONTEMPORARY PN POPULATION

Less than 1%

RENAL ISCHEMIA – TAKE HOME

• Limited ischemia is safe to perform partial

nephrectomy

• Overly simplistic and naïve to consider a single

value ischemia time cut off to act as a

dichotomous marker for renal injury

• Do not compromise the main goal while

performing PN - Sound and Safe Oncologic

outcomes

TECHNICAL MODIFICATIONS - ISCHEMIA

• No high level data showing unequivocal benefit of cold

over warm

• Animal , transplant and retrospecitve human studies

suggest protective effect of hypothermia

• Temperature and techniques remain dependent on

institution and surgeon

• Early unclamping , Off-clamp PN , Selective clamping ,

Zero ischemia etc …

• Not Necessary

Porpiglia et al BJUI 2015

Increased blood loss with zero ischemia

approach

No difference in renal functional outcomes

between clamp and zero ischemia

approaches

ANATOMIC STUDY OF RENAL ARTERIAL VASCULATURE AND ITS

POTENTIAL

IMPLICATION ON PARTIAL NEPHRECTOMY

Machhi et al, BJUI January 2017

• In 80% of patients, one single renal

segment was vascularized by 2 or

more different branches coming from

an artery destined to another

segment

ANATOMIC STUDY OF RENAL ARTERIAL VASCULATURE AND ITS

POTENTIAL

IMPLICATION ON PARTIAL NEPHRECTOMY

Machhi et al, BJUI January 2017

TECHNICAL MODIFICATIONS TO MAXIMIZE PARENCHYMAL

PRESERVATION

• Enucleation

• Blunt dissection along the pseudocapsule

without excision of a rim of normal

parenchyma

• Oncological outcomes appear safe

• Non-renorrhaphy technique

• No cortical suturing to minimize

parenchymal damage

• No evidence of benefit

TAKE HOME MESSAGE

• Pre and post operative preparation important

• Baseline quality and post operative quantity of

renal parenchyma critical

• Renal ischemia safer than earlier thought

• Surgical modifications helpful but must be

balanced by oncologic efficacy and morbidity

• Mir MC et al. Current paradigm for ischemia in kidney surgery.

J Urol, 2016.

• Rod et al. Impact of ischemia time on renal function after

partial nephrectomy: a systematic review. BJUI, 2016

• Volpe A et al. Renal ischemia and function after partial

nephrectomy: A collaborative review of the literature. Eur Urol,

2015

• Mir MC et al. Decline in renal function after partial

nephrectomy: Etiology and prevention. J Urol, 2015.

• Kim SP et al. Kidney function after partial nephrectomy:

Current thinking. Curr Opin Urol 2013.

• Parekh DJ et al. Tolerance of the human kidney to isolated

controlled ischemia. JASN, 2013.

SUGGESTED READING

Good to Great

In his famous essay “The Hedgehog and the

Fox,” Isaiah Berlin

divided the world into

hedgehogs and foxes,

based upon an ancient Greek parable: “The fox

knows many things, but

the hedgehog knows one big thing.”

What are you

deeply passionate

about

What you can

be the best in

the world at

What drives

your

economic

engine

Jim Collins

3 circles of the Hedgehog concept