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Sepsis Associated AKI (w/audio)

Nordic/Baltic CRRT symposium 2015
by

Niklas Jonsson

on 17 January 2016

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Transcript of Sepsis Associated AKI (w/audio)

Sepsis Associated AKI
Dr. Niklas Jonsson, dept of Anesthesiology & Intensive Care
Karolinska University Hospital

Paradigm shift!
Hypothesis historically
Q & A today:
Cell adaptation
Recent advances in knowledge
Microcirculation not macrocirculation
Tubular cells don't die, they adapt to survive
Epidemiology
Tubular cell adaptation not tubular necrosis
DAMPs, PAMPs and inflammation
Renal blood flow decreases
Experimental
ischemia, ATN
Improve cardiac output & renal blood flow
Hypothesis now
Renal blood flow unchanged or increased
How can SA-AKI occur without previous shock?

Why is GFR reduced when cardiac output is ok?

How can we protect the kidneys from AKI in sepsis?
In Vitro
Post Mortem
AKI is prevalent even in populations with pneumonia, without hypotension
Induced sepsis in sheep resulted in AKI but unchanged or increased renal blood flow was seen
AKI-like changes were induced by exposing cultured tubular cells and podocytes to plasma from septic patients
Histological tissue samples from deceased SA-AKI patients do not show Acute Tubular Necrosis
The renal cells adapt to the new, harmful environment
Damage Associated Molecular Patterns
DAMPs & PAMPs
Inflammatory mediators i.e. Lipopolysacharid, cytokines
Pathogen Associated Molecular Patterns
Triggers cells via Toll-like receptors (TLR-2, TLR-4), NOD-like receptors och RIG-I-like receptors
Proximal tubuli sense DAMPs/PAMPs first & signals to distal segments
Tubular cells respond w/ oxidative stress which starts an adaption to reduced metabolism
This adaptation can shut down the mitochondria; cellcycle arrest
Mitochondria shutdown in tubular cells start shutdown of cellular functions (absorb & secrete particles)
Cell cycle arrest
Cells shut down mitosis to save energy
and avoid damage to DNA
Reduces risk of apoptosis due to damage or energy depletion
Damaged mitochondria are destroyed through autophagocytosis; a.k.a. mitophagy
Necessary functions for membranepotential like Na/K ATPase, remain
Experimental inhibition of mitophagy aggravates tissue damage and stimulation reduces tissue damage
Great oxidative stress can result in cell necrosis and apoptosis
Peritubular capillaries w/ continuous flow decrease and capillaries w/ intermittent flow increase
iNOS
Inducable Nitric Oxide Synthetase
Catalyst for NO-production
NO is a free radical used by the immune system against bacteria
NO dilates blood vessels and causes shunting
NO mediates activation of renal Caspases (induce tubular apoptosis)
iNOS has a heterogeneous spread in the tissue, correlates to the spread of microvascular dysfunction
Inhibition of iNOS reduces AKI, both histologically and functionally
Relative efferent vasodilatation:
Dilatation in both afferent and efferent arterioli due to NO
Some (relative) vasoconstriction in the afferent arterioli (due to tubuloglomerular feedback?)
Reduces the hydrostatic pressure in the glomerulus
Epidemiology of SA-AKI
40% of patients come to the ICU because of sepsis
40-50% of septic patients get AKI (most probably SA-AKI)
Severity of sepsis related to incidence of AKI:
Sepsis 4.2%, severe sepsis 22.7%, septic shock 52.8%
Outcome of SA-AKI
Death in ICU/In-hospital death
Mortality based on RIFLE
Loss of GFR caused by efferent vasodilatation
Acute kidney injury in non-severe pneumonia is associated with
an increased immune response and lower survival, Murugan et al 2010
Glomerular haemodynamics, the renal sympathetic nervous
system and sepsis-induced acute kidney injury, Calzavacca et al 2014
Hypotension not independently associated w/ SA-AKI
Elevated Plasma Concentrations of IL-6 and Elevated APACHE II Score Predict Acute Kidney Injury in Patients with Severe Sepsis, Chawla et al 2007
Sepsis-induced renal dysfunction was reversed by TLR4 inhibitor
Reduced renal neutrophil infiltration
Attenuated sepsis-induced endothelial swelling
Creatinine, BUN, creatinine clearance, urine production and filtration fraction
Renal effects of treatment with a TLR4 inhibitor in conscious septic sheep, Fenhammar et al 2014
No significant tubular damage
Alteration of polarity in tubular cells
Reduced expression of the tight junction protein ZO-1
Podocytes showed increased permeability to albumin
Reduced expression of endocytic receptor megalin

Circulating plasma factors induce tubular and glomerular
alterations in septic burns patients, Mariano et al 2008
The histopathology of septic acute kidney injury: a systematic review, Langenberg 2008
In fact, postmortem studies of deceased SA-AKI patients showed only gentle histological changes
Role of apoptotic cell death in sepsis, Hotchkiss et al, 2003
Renal histopathology during experimental septic acute kidney injury and recovery, Langenberg 2014
A, B Controls
C, D SA-AKI
Handwrittentutorials.com
What about shunting?
Described by Arne Ljungqvist
in 1964!
"The vascular arrangement of the juxtamedullary arterioleglomerular unit can therefore be regarded as a potential intrarenal regulatory mechanism of glomerular filtration rate (GFR) and filtration fraction (FF)"
Ultrastructural demonstration of a connection between afferent and efferent juxtamedullary glomerular arterioles, Ljungqvist 1975
Structure of the arteriole-glomerular units in different zones of the kidney. Microangiographic and histologic evidence of an extraglomerular medullary circulation, Ljungqvist 1964
EA Efferent Arteriole, PC peritubular capilarries, AA Afferent Arteriole, AV Arteriovenous vessel, IA Interlobular Artery
Maybe, just maybe...
...millions of years of evolution was a success?
... and the shunt has a purpose?
Afferent arteriole
Vasa recta
Can't we give a selective efferent arteriole vasoconstrictor?
Yes we can!
Angiotensin II in a sheep sepsis model restored urinary production, creatinine
Angiotensin II in experimental hyperdynamic sepsis, Wan et al 2009
Vasopressin is also an efferent vasoconstrictor:
4 RCT's, including VASST, showed improved urinary output and creatinine clearance with Vasopressin vs NE
VANISH study to be complete in May 2015
Protocol for a randomised controlled trial of VAsopressin versus Noradrenaline as Initial therapy in Septic sHock (VANISH), Gordon et al 2014
Continuous terlipressin versus vasopressin infusion in septic shock (TERLIVAP): a randomized, controlled pilot study, Morelli et al 2009
Beneficial effects of short-term vasopressin infusion during severe septic shock, Patel 2002
Vasopressin or norepinephrine in early hyperdynamic septic shock: a randomized clinical trial, Lauzier 2006
Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock, Russel 2008
Early antibiotics
Acute kidney injury in septic shock: Clinical outcomes and impact of duration of hypotension prior to initiation
of antimicrobial therapy, Bagshaw 2009
Retrospective cohort study
4532 subjects
Negative fluid balance
A positive fluid balance is associated with a worse outcome
in patients with acute renal failure. Payen et al 2008
Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure
are associated with increased mortality. Boyd et al 2011
Fluid overload in AKI is an independent predictor of mortality & worse renal recovery
Predictor of death when CRRT fails to remove fluid within 3 days
Early CRRT to attenuate fluid overload reduces mortality
VASST: optimal w/ 3 l + after 12 h then neg fluid balance
Fluid overload a "biomarker" of critical illness
Fluid overload before continuous hemofiltration and survival in
critically ill children: A retrospective analysis, Foland 2004
Avoid renal congestion
Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study, Payen 2013
Higher CVP in the first 24 hours of septic shock linearly associated with increasing risk of new or persistent AKI
Increased renal venous back pressure reduces diastolic perfusion
Diastolic perfusion pressure probably a key determinant of renal perfusion
Hyperpermeability and inflammatory cell adherence in SA-AKI also increase renal interstitial pressure
5 mmHg increase in CVP predicted 2.7-fold odds of new or persistent AKI
Open lung ventilation
Barotrauma releases DAMPs!
1/4 of cardiac output passes the kidneys
In ARDS, lung protective ventilation reduced AKI
SA-AKI is an inflammatory disease of the
renal microcirculation
"Oliguria in sepsis isn't a renal failure,
it's a renal success"
Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome, Ranieri et al 2000
ARDSNet: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome, 2000
TNF-α, IL-1b, IL-6, and IL-8
Haemofiltration
Yes, for fluid removal!
Maybe, to get rid of some DAMPs and PAMPs (expert opinion)
No benefit from high dose > 45 ml/kg/h compared to standard dose*
Timing: One RCT showed no difference in outcome.
Two ongoing studies; STARRT-AKI and IDEAL-ICU
RENAL study, 2009
ATN study 2008
CRRT shows better renal recovery compared to IHD in vasopressor dependent patients
Acute kidney injury in patients with sepsis and septic shock: risk factors and clinical outcomes, Suh et al 2013
Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: a prospective, randomized trial, Bouman et al 2002
The usual suspects
Avoid NSAIDs
Avoid ACE inhibitors
Retrospective studies support early dialysis
Avoid normal saline and hyperchloremic acidosis (impairs renal perfusion by causing vasoconstriction of the afferent arteriole)
Avoid too much Gensumycin and Vancomycin
Caspase inhibitor reduced apoptosis and preserves kidney function in mice with SA-AKI
IL-10 antibodies to inhibit T-regulatory cells reduced AKI in sepsis but not in ischemia/reperfusion, also in mice
Selective efferent vasopressors preserve GFR in sepsis AKI (RCT ongoing; VANISH)
Alkaline phosphatase; detoxifies LPS and degrades extracellular ATP (harmful)
to adenosine (protective)
What does the future hold?
Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial, Pikkers 2012
Ghrelin reduced SA-AKI in mice by binding and inhibiting DAMPs
Levosimendan causes dilatation of afferent but not efferent arteriole. RCT ongoing; LeoPARDS
Vagus nerve stimulation decreases the release of proinflammatory mediators from the spleen and reduces AKI
Clinical trial with TLR-4 inhibitor (TAK-242)? (Eritoran didn't show benifit)
1. Sepsis causes downregulation of Na/K/Cl co-transportation in proximal tubuli
2. Rising NaCl-konc in distal tubuli
3. Macula Densa demands (relative) vasoconstriction in afferent arterioles = GFR
4. Paracrine signal to juxtaglomerular cells to reduce Renin secretion
Tubuloglomerular feedback
The Macula Densa controls GFR depending on
NaCl-konc in distal tubuli:
niklas.jonsson@karolinska.se
Twitter : @DoctorNikko
Full transcript