ICN VIctoria: John Botha on Critical Care Renal Failure

PENINSULA HEALTH
c12 classification by the College of Intensive Care
Medicine
• The Problem with Acute Renal Failure
• John Botha
• MBChB M Med FCP(SA)FRACP FCICM Dip PG Echo Dip Neph
• Director of Intensive Care Peninsula Health
• Adjunct Clinical Professor Monash University
Peninsula Health, Winner – Metropolitan Health Service of the Year 2007 and 2009
2

Why is Hospital Acquired AKI a problem
for the bedside clinician?
• Renal Physiology is Complex
• Markers of Renal Injury are not clinically used(or useful?)
• Fluid management in Sepsis is Difficult and overzealous
administration is bad
• The role of the endothelial glycocalyx in fluid distribution is
important and its integrity is difficult to measure
• Fluid Types may impact on Renal Outcome
• Therapies for AKI with RIFLE Risk and Injury are limited
• High Intensity RRT has not proven benefit
• Optimising Filter life is problematic
• In patients who have RRT in ICU the outcomes is poor

Problematic physiology
1. The kidney is at risk of
hyperoxia
2. The kidney is at risk of
hypoxia

• The kidney has a high exposure to O2
• Oxygen tension is tightly regulated in all organs
because high PO2 is toxic
• In the kidney superoxide production is tightly
dependent on O2 availability

• The human kidney has structural antioxidant
defences.
• Arteries and veins are closely associated
• This facilitates counter-current diffusion and
enables a high degree of AV shunting

Renal veins have a unique peri-arterial structure
It facilitates diffusive O2 shunting

Close coupling of veins and arteries to achieve counter-current O2 diffusion

This shunting is dependent on Renal Blood Flow

The cortex and the medulla
Are linked by shunting
If the cortex is underperfused
More AV shunting occurs in
interlobular vessels
This can lead to medullary ischemia
Even if medullary flow is preserved

The septic kidney: global renal blood flow

Intra-renal blood flow
In septic sheep

Intra-renal oxygenation
Cortico-medullary dissociation
Knowing global
Or even intra-renal blood flow says
little about medullary oxygenation

Clinical implications
• Global renal blood flow may be dissociated from
GFR, medullary flow and medullary O2
• Reliable ways to measure renal blood flow are not
available
• If there were reliable therapies to increase renal
blood flow the effect of this on GFR is unpredictable.
• The renal medulla is always at risk of hypoxia

Biomarkers for the prediction of acute kidney injury: a narrative review on
current status and future challenges
Hilde R. H. de Geus, Michiel G. Betjes and Jan Bakker Clin Kidney J (2012) 5
(2): 102-108
Biomarkers for AKI
• Functional markers- SCr and plasma/serum CyC
• Up-regulated proteins -NGAL, KIM-1, L-FABP and IL-18
• Low-molecular weight proteins -Urine CyC
• Enzymes NAG,- a-GST, p-GST, GGT and AP
Markers of Renal Injury are not clinically
used(or useful?)

The reported AUCs are disappointing ranging from 0.50 to 0.84, with one
or two exceptions, which can be explained by statistical or
methodological differences in study design.
The discriminatory function in heterogeneous populations is poor and
influenced by pre-existing renal function and time of sample
collection with respect to the renal insult
Clinical appraisal of a patient using standard parameters such as
SCr and diuresis remains the cornerstone for now
Reasonable to use biomarkers together with other parameters such as
traditional clinical characteristics to optimize the accuracy of prediction of
developing AKI

Acute Renal Failure in the Critically Ill
Multinational Multicentre Study JAMA August 17 2005 Vol 294
Septic
Shock
Major
Surg
Cardio
Shock
Hypo
Vol
Drug HRS Obstr
Uro
Other
47.5% 34.3% 26.9% 25.6% 19% 5.7% 2.6% 12.%

MORTALITY
0%
10%
20%
30%
40%
50%
60%
ICU WARD

Fluid management in Sepsis is Difficult and overzealous administration is bad
Fluid resuscitation in septic shock-
A positive fluid balance and elevated central venous
pressure are associated with increased mortality
• Boyd, John H. MD, FRCP(C); Forbes, Jason MD; Nakada, Taka-
aki MD, PhD; Walley, Keith R. MD, FRCP(C); Russell, James A.
MD, FRCP Critical Care medicine Feb 2011 Vol 32

Design
• VASST Study Patients: The Vasopressin in Septic
Shock Trial (VASST) study enrolled 778 patients who
had septic shock
• A retrospective review of the use of intravenous
fluids during the first 4 days of care.

• Based on net fluid balance, they determined
whether fluid balance quartile correlated with
28-day mortality

Table 1
Table 1. Fluid intake, urine output, and net
fluid balance at 12 hrs and cumulative day
4 balance
Copyright © 2011 Critical Care Medicine. Published by Lippincott Williams & Wilkins. 31
Fluid resuscitation in septic shock: A
positive fluid balance and elevated central
venous pressure are associated with
increased mortality*
Boyd, John H.; Forbes, Jason; Nakada, Taka-
aki; Walley, Keith R.; Russell, James A.
Critical Care Medicine. 39(2):259-265,
February 2011.
doi: 10.1097/CCM.0b013e3181feeb15

Figure 2
Figure 2.A, Cox survival curves, adjusted for age, Acute
Physiology and Chronic Health Evaluation (APACHE) II
score, and severity of shock (dose of norepinephrine),
are shown for fluid balance quartiles
at 12 hrs.
Quartiles 3 and 4 have significant
increases in mortality compared with
both quartiles 1 and 2
. B, Cox survival curves, adjusted for age, APACHE II
score, and dose of norepinephrine, are shown for
cumulative fluid balance quartiles at
day 4. Quartiles 3 and 4 have
significant increases in mortality
compared with both quartiles 1 and 2.

Table 2
Table 2. Hazard ratio for death according to
fluid balance quartiles
Fluid resuscitation in septic shock: A
positive fluid balance and elevated central
venous pressure are associated with
increased mortality*
Boyd, John H.; Forbes, Jason; Nakada, Taka-
aki; Walley, Keith R.; Russell, James A.
Critical Care Medicine. 39(2):259-265,
February 2011.
doi: 10.1097/CCM.0b013e3181feeb15

• A more positive fluid balance both early in
resuscitation and cumulatively over 4 days is
associated with an increased risk of mortality
in septic shock

Next Question.
• Whether fluid balance was predictive of
central venous pressure ?
• Whether a guideline-recommended central
venous pressure of 8–12 mm Hg yielded a
mortality advantage?

Figure 3
B, Day 4 fluid balance during the preceding 24 hrs does
not correlate with central venous pressure nor with the
dose of norepinephrine.
Figure 3.A, Fluid balance on study enrolment (12
hrs) significantly correlates with central venous
pressure and dose of norepinephrine, p < .001 in
both cases.

Figure 4
. B, Cox survival curves, adjusted for age, APACHE II score,
and dose of norepinephrine, are shown for CVP groups on
day 4. There were no significant differences in mortality
among groups.
Cright © 2011 Critical Care Medicine.
Published by Lippincott Williams &
Wilkins.
37
Figure 4.A, Cox survival curves, adjusted for age,
Acute Physiology and Chronic Health Evaluation
(APACHE) II score, and severity of shock (dose of
norepinephrine), are shown for central venous
pressure (CVP) groups at 12 hrs. Patients with
a CVP of <8 mm Hg at 12 hrs have the lowest
mortality followed by those with CVP of 8–12
mm Hg and patients with a CVP >12 mm Hg
had the highest mortality

• Central venous pressure correlated with fluid balance at 12 hrs.
• On days 1–4, there was no significant correlation.
• At 12 hrs, patients with a central venous pressure <8 mm Hg had
the lowest mortality rate followed by those with central venous
pressure 8–12 mm Hg. The highest mortality rate was observed
in those with central venous pressure >12 mm Hg.
• There was no correlation between CVP and mortality at day 4

• However, in patients whose central venous pressure was <8
mm Hg
• Found a more positive fluid balance among survivors
compared with non survivors
• Suggesting that there is a point at which too little fluid is
indeed harmful

The Elusive Sweet Spot !!!!
©

Then of course how to administer the fluid?

A positive fluid balance is associated with a worse outcome in patients with
acute renal failure.
Payen D, de Pont AC, Sakr Y, Spies C, Reinhart K, Vincent JL; Sepsis Occurrence in Acutely Ill
Patients (SOAP) Investigators. Crit Care. 2008;12(3):Jun 4.

An observational study fluid balance and patient outcomes in the Randomized
Evaluation of Normal vs. Augmented Level of Replacement Therapy trial.
RENAL Replacement Therapy Study Investigators,

Improved understanding of microvascular physiology allows explanation of the
discrepancy between clinical findings during fluid therapy and the original
Starling principle
The role of the endothelial glycocalyx in fluid distribution is important and its
integrity is difficult to measure

MATERIAL AND METHODS: A total of 150 individuals were tested for levels of inflammatory markers
(intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], interleukin-6
[IL-6]) and glycocalix markers (syndecan-1, heparan sulfate). Three groups consisted of patients with
severe sepsis or septic shock, patients after major abdominal surgery without systemic
inflammatory response syndrome, and healthy volunteers. Blood was drawn, at the time of diagnosis
or surgery, and 6, 24, and 48h later.
RESULTS: Levels of inflammatory markers were markedly higher in patients with sepsis compared with
patients after major abdominal surgery and healthy volunteers. After major abdominal surgery,
glycocalix markers in human plasma were at levels comparable to patients with sepsis. In patients
with sepsis, levels of IL-6 correlated with syndecan-1, ICAM-1, VCAM-1, and lactate, while ICAM-1
furthermore correlated with CRP and lactate levels.
CONCLUSION: High levels of glycocalix markers indicated that significant flaking of the endothelial
glycocalix occurred in patients with sepsis, and to a lesser extent in patients after major abdominal
surgery. This novel finding could explain the nonspecific capillary leaking syndrome of patients with
sepsis and after major abdominal surgery, and may identify new targets for treating those patient
populations.

Natriuretic Peptide in the Critically Ill with Acute Kidney Injury
Massimo de Cal, Mikko Haapio, Dinna N. Cruz, Paolo Lentini, Andrew A. House,
Ilona Bobek, Grazia M. Virzì, Valentina Corradi, Flavio Basso, Pasquale Piccinni,
Angela D'Angelo, Jamie W. Chang, Mitchell H. Rosner, and Claudio Ronco Int J
Nephrol. 2011; .
Increase in median of BNP of patients with AKI on admission

• In this pilot study, demonstrated for the first
time an association between plasma BNP
levels and AKI in critically ill patients.
• Patients with AKI have higher levels of BNP
compared to no-AKI patients, and in AKI
patients BNP levels continue to increase during
the subsequent 48 hours.
• Results suggest that plasma BNP may
distinguish the occurrence of AKI.

Fluid Type may impact Renal Outcome

Resuscitation fluid use in critically ill adults: an
international cross-sectional study in 391 intensive care
units
Simon Finfer, Bette Liu, Colman Taylor, Rinaldo Bellomo, Laurent Billot, Deborah
Cook, Bin Du, Colin McArthur, John Myburgh and SAFE TRIPS Investigators

Percentage of fluid resuscitation episodes given as
crystalloid, colloid or blood product according to
country

Type of colloid used as a percentage of all colloid episodes by country.

• Loop diuretics
• Mannitol
• Dopamine
Therapies for AKI with RIFLE Risk and Injury are limited

AIM
The primary aim of the study is to assess the effects of a continuous supplementary
infusion of standard L-amino acids on renal function, renal failure and recovery from
renal injury in critically ill patients who require at least three days of intensive care.
The effects of a continuous supplementary infusion of a standard mixture of L-amino
acids will be compared to standard care with regards to the onset and severity of
clinically significant renal dysfunction, need for RRT, renal recovery rates, need for
ongoing dialysis, and health status (quality of life, physical function and overall survival) at
follow-up 90 days after randomisation.
Nephro-protective effects of L-amino acids in critically ill patients:
A multi-centre randomised controlled trial. Gordon S. Doig, Fiona Simpson,
Elizabeth Sweetman, Philippa Heighes, Rinaldo Bellomo, Michael Reade,
Peter Harrigan, Andrew Davies,Carol Pollock, John Botha, Douglas Chesher,
and Prasad Devarajan

Therapeutic agents for the treatment of AKI
Anti-inflammatory agents
b1 Integrin antagonist, adenosine receptor
antagonist, mesenchymal stem cells, C5a
receptor antagonist, IL-10, IL-6 antagonist,
statins, erythropoietin, a melanocyte stimulating
hormone, haeme oxygenase-1 inducers
(rapamycin), activated protein C, toll like receptor
(TLR) blockers (Eritoran), sphingosine 2A agonist,
fibrates, statins, peroxisome proliferator
activared receptor (PPAR)-c agonist, minocycline,
inducable nitric oxide (iNOS) inhibitor, insulin,
ethyl pyruvate, C5-antagonists,
alkaline phosphatase
Anti-apoptotic agents NGAL, adenosine receptor antagonist,
mesenchymal stem cells, erythropoietin,
a-melanocyte stimulating hormone, caspase
inhibitors, minocycline, guanosine, pifithrin-a,
poly ADP ribose polymerase (PARP) inhibitor
Iron scavengers NGAL, apotransferrin, deferoxamine
Anti-oxidants Edavarone, stobadine, deferoxamine
Vasodilators Endothelin receptor antagonist, fenoldopam, anti natriuretic peptide
Growth factors Erytropoetin, hepatocyte growth factor
?

0%
10%
20%
30%
40%
50%
60%
Never Seldom Sometimes Often Always
Use of Frusemide
Lasix Bolus Lasix Infusion
What happens in practice?

Mean Arterial Blood Pressure targeted
0
20
40
60
80
100
120
60-70 70-80 >80

Nephrology consult
0
10
20
30
40
50
60
70
Never Seldom Sometime Often Always

Central Venous Pressure Monitoring
Monitor CVP
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Never Seldom Sometimes Often Always

DOSE OF RRT: The VA/NIH STUDY
Intensity of Renal Support in Critically ill Patients
High Intensity RRT has no proven benefit

Randomisation
Intensive Management
Intermittent haemodialysis 6 times
a week
If hemodynamically unstable
CVVHDF 35 ml/kg/hr
Conventional Management
3 times a week
CVVHDF 20ml/kg/hr
END POINT
Primary Endpoint
60 day all cause
mortality

Primary Outcome
Death from any cause by day 60:
Intensive Strategy (53.5%)
Less Intensive Strategy (51.5%)
(P Value 0.57)

Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients
The RENAL Replacement Therapy Study Investigators
N Engl J Med 2009; 361:1627-1638

Trial Management, Grant Applicants
Rinaldo Bellomo
Celia Bradford
David Gattas
Dorrilyn Rajbhandari
Statistician
Serigne Lo – George Institute
7 TRIAL SITES
Auckland City (NZ)
Shay McGuinness, Rachael Parke
Austin (VIC)
Rinaldo Bellomo, Glenn Eastwood
Dandenong (VIC)
Sanjiv Vij, Katherine Shepherd, Bridget O’Bree
Frankston (VIC)
John Botha, Sharon Allsop, David Lewis
Monash (VIC)
Craig Walker, Pauline Galt, Tammy Lamac
Royal North Shore (NSW)
Celia Bradford, Anne O’Connor
Royal Prince Alfred (NSW)
David Gattas, Dorrilyn Rajbhandari, Heidi Buhr
SLHD (RPAH Zone) HREC Approval: X09-0068 & HREC/09/RPAH/98
The Heparin Citrate (THC) Study
Optimising Filter life is problematic

AIM
To test the hypothesis that
regional citrate anticoagulation
is more effective than
regional heparin/protamine
anticoagulation
at maintaining functional filter life
in patients receiving CRRT
The Heparin Citrate Study ACTRN 12609001079235

INCLUSION
Commencing CRRT for acute
renal failure
Suitable for intervention or
control
Equipoise
Consent (prior or delayed)
At least 1 of: K>6.5, pH<7.2,
urea>25, creatinine >300,
oedema
Age <18y
Expected <24h in ICU
Contraindication to
intervention or control (eg
liver, H.I.T)
Expected difficulty adhering to
allocated group
EXCLUSION

INTERVENTION
Regional citrate
anticoagulation
Regional
heparin/protamine
anticoagulation
CONTROL
CRRT CIRCUIT ANTICOAGULATION
Between Sites: Different hardware, modalities, protocols
Within Sites: Same hardware, modality. Same/v similar
starting blood flow and fluid flow rates
Unblinded (statistician was blinded)

PRIMARY OUTCOME
Functional filter life
transmembrane pressure >300mmHg
visible clot obstructing flow / blood pump
other reason (free text)
Measured in time to clotting event (hours)
All free text reasons for stopping were adjudicated
by 2 independent, blinded intenvisists, and any
disagreements resolved by consensus
Deemed by consensus: clotted, didn’t clot, or unsure

RESULTS
Baseline Characteristics – diagnosis and severity
Table. Baseline characteristics of the intervention and control group
Citrate (N=105) Heparin/protamine (N=107)
~ 12% cardiac surgery, ~8 %septic shock,
well matched groups including severity of illness
APACHE III Diagnostic Group - no./total (%)
Coronary artery bypass grafts 14/105 (13.3) 13/107 (12.1)
Renal disorders 10/105 (9.5) 7/107 (6.5)
Sepsis with shock, non-urinary 8/105 (7.6) 7/107 (6.5)
Other respiratory diseases 6/105 (5.7) 7/107 (6.5)
Valvular heart surgery 5/105 (4.8) 6/107 (5.6)
Other 62/105 (59.0) 67/107 (62.6)
APACHE II score - mean(SD) 25.6 (7.6) 25.0 (6.9)
Meeting criteria for severe sepsis - no./total (%) 45/105 (42.9) 32/107 (29.9)
SOFA: patients scoring 3+ at time of randomisation, no./total (%)
Renal 45/101 (44.5) 51/106 (48.1)
Cardiovascular 69/101 (68.3) 68/106 (64.2)
Respiratory 46/101 (45.5) 51/106 (48.1)
Coagulation 5/101 (5.0) 3/106 (2.8)
Liver 3/101 (3.0) 7/106 (6.6)

RESULTS
Baseline Characteristics – vent, inotrope, labs
Table. Baseline characteristics of the intervention and control group
Citrate (N=105) Heparin/protamine (N=107)
~73% patients ventilated, ~67% inotropes
Well matched at baseline for renal and haematological parameters
Mechanically ventilated - no./total (%) 77/105 (73.3) 75/107 (73.3)
Receiving inotropes - no./total (%) 74/105 (68.4) 71/107 (66.4)
Renal parameters - mean (SD)
Urea (mmol/L) 21.9 (13.3) 23.4 (13.8)
Creatinine (µmol/L) 309 (157) 322 (177)
Phosphate (mmol/L) 2.02 (0.83) 1.94 (0.94)
Urine output in 6h prior to randomisation (mL) 170 (262) 190 (222)
Haematological parameters - mean (SD)
Haemoglobin (g/L) 98.0 (16.6) 98.3 (26.2)
Platelet count (x10^9/L) 209 (146) 215 (143)
INR 1.5 (1.2) 1.4 (0.52)
APTT (s) 40 (18) 40 (14)

RESULTS
Primary Outcome
The Heparin Citrate Study ACTRN 12609001079235 • Includes the first filter in each patient ONLY
Citrate median 39h (100 filters*)
vs
Hep/prot median 22.8h (104 filters*)
Log rank p= 0.0037

RESULTS
Number of Filters, Duration of CRRT
The Heparin Citrate Study ACTRN 12609001079235 * filter outcome adjudicated by 2 independent intensivists
Regional citrate anticoagulation was associated with
use of fewer filters, less clotted filters and
longer cumulative duration of CRRT
Number of filters included in the study*
Citrate
Heparin/
protamine
Total
Clotted 226 310 536
Didn't Clot 127 112 239
Unclear 37 45 82
TOTAL 390 467 857
Duration of CRRT (hours) 8281 8015 16296

RESULTS
Primary Outcome
Frailty Model Analysis: Hazard Ratios for FilterGroup
Description Point Estimate95% Wald Confidence Limits
FilterGroup Hep/Prot vs Citr 2.029 1.359 3.028
Analysis of Maximum Likelihood Estimates
Parameter DF
Parameter
Estimate
Standard
ErrorChi-SquarePr > ChiSq
Hazard
RatioLabel
FilterGroup Hep/Prot 1 0.70736 0.20429 11.9888 0.0005 2.029FilterGroup 0
The hazard ratio for a filter experiencing clotting in the
heparin/protamine group (compared to citrate) was
2.03 (95% CI 1.34-3.02, p<0.005)
Filters in the citrate group are half as likely to clot
Cox model with random effect by subject

CONCLUSION
During CRRT in ICU,
regional citrate anticoagulation,
compared to regional heparin/protamine anticoagulation
is associated with
- Half the risk of filter clotting
[HR for clotting in hep/prot group 2.03 (95% CI 1.34-3.02, p<0.005)]
- Median filter life 39h v 22.8h (p=0.0037)
- Fewer adverse events

In patients who have RRT in ICU What about their outcome?

Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in Intensive
Care: Extended Follow-up of a Randomized Controlled Trial
Martin Gallagher Alan Cass, Rinaldo Bellomo, Simon Finfer, David Gattas, Joanne Lee,
Serigne Lo, Shay McGuinness, John Myburgh, Rachael Parke, Dorrilyn Rajbhandari, for
the POST-RENAL Study Investigators and the ANZICS Clinical Trials Group Membership of
the POST-RENAL. February 11, 2014 PLOS medicine

Figure 2. Kaplan-Meier survival curve for all study participants from randomization to end of
extended follow-up, shown by treatment group.
Gallagher M, Cass A, Bellomo R, Finfer S, et al. (2014) Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in
Intensive Care: Extended Follow-up of a Randomized Controlled Trial. PLoS Med 11(2): e1001601.
doi:10.1371/journal.pmed.1001601

Table 5. Cox multivariate model for long-term mortality from randomization.
Gallagher M, Cass A, Bellomo R, Finfer S, et al. (2014) Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in Intensive
Care: Extended Follow-up of a Randomized Controlled Trial. PLoS Med 11(2): e1001601. doi:10.1371/journal.pmed.1001601

Table 4. Prevalence of CKD by eGFR and albumin to creatinine ratio in follow-up participants.
Gallagher M, Cass A, Bellomo R, Finfer S, et al. (2014) Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in
Intensive Care: Extended Follow-up of a Randomized Controlled Trial. PLoS Med 11(2): e1001601.
doi:10.1371/journal.pmed.1001601
http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001601

Found that patients with AKI treated with RRT in the ICU were at high risk of
dying during the 3.5-year follow-up period; overall 31.9% of those surviving to 90
days died during the extended follow-up period.
The risk of dying was much greater than the risk of entering a maintenance
dialysis program, with neither outcome being influenced by the use of a higher
intensity of RRT.
The rate of albuminuria in survivors was substantial, despite relative preservation
of renal function

• Consider causes other than ATN.
• Be mindful of Nephrotoxic drugs.
• Restore MAP and ignore CVP after a few days in ICU
• Fluid overload is bad and fluid therapy in ICU is a
dynamic process.
• After initial resuscitation aim for a neutral or negative
fluid balance
• Synthetic colloids should be avoided
• Consider Citrate
• Follow up of survivors should be considered with
attention to strategies to decrease albuminuria

PENINSULA HEALTH
• Thank You
Peninsula Health, Winner – Metropolitan Health Service of the Year 2007 and 2009
2

ICN VIctoria: John Botha on Critical Care Renal Failure

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ICN VIctoria: John Botha on Critical Care Renal Failure