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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