The Ins and Outs of Acute Kidney
Injury: pathophysiology, clinical
relevance and new concepts
Ayla R. Preston, DVM, MS
Practice Limited to Emergency and Critical Care
Background
• Clinical problem in the critically ill
• Acute kidney injury (AKI) defined
▫ Acute reduction in function that may only be
reflected by small increases in serum creatinine
• Mortality of AKI
▫ Human medicine
 ~50%
▫ Veterinary medicine
 ~60% in dogs
 ~64% in cats
Background
• Why not acute renal failure (ARF)?
▫ ARF = rapid, sustained decrease in renal function
▫ Not very specific
▫ Diagnose ARF when patient is azotemic
• Why AKI?
▫ First termed by the Acute Kidney Injury Network
(AKIN)
▫ Incorporates entire spectrum of ARF
▫ Identifies minor changes in renal function (important)
▫ Has prognostic indications
Pathophysiology
• Decreased renal function in AKI is multifactorial
and complex at the cellular level
▫ Decreased intrarenal blood flow
▫ Cellular damage
Pathophysiology
• Four phases of AKI
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Initiation
Extension
Maintenance
Recovery
Pathophysiology
• Initiation phase
▫ When pathologic damage is initiated
▫ May not have abnormal laboratory values
▫ Pre-renal causes
 Shock, hypotension, dehydration
▫ Renal causes
 Ischemia, infarction, toxins, infectious diseases,
drugs , HES, acute pancreatitis, MODS
▫ Post-renal causes
 Urolithiasis, urethral obstruction, uroabdomen
Pathophysiology
• Extension
▫ Downstream effects of the initial event
(propagation)
▫ Laboratory abnormalities may not be evident
▫ Mechanisms can be complex and depend upon
underlying etiology
 Ischemia, inflammation, oxidative damage, tubular
dysfunction, cellular hypoxia, etc.
Pathophysiology
• Maintenance
▫ May last for days to weeks
▫ Characterized by:
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Azotemia
Uremia
Combination
Variable urine production
▫ Nephron dysfunction may continue from
mechanisms described in the extension phase
Pathophysiology
• Recovery
▫ Renal tubules can undergo repair
▫ Azotemia improves
▫ May or may not have complete return of “preinjury” renal function
▫ Patients generally very polyuric during this phase
of AKI
Risk factors for AKI
• Hetastarch
▫ Growing evidence to support this in people
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Fluid overload
Hypotension
Infarction
Ischemia
Renal toxic drugs
▫ Aminoglycosides
▫ NSAIDs
• Infectious diseases
Poor prognostic indicators (dogs)
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Creatinine > 10 mg/dL
Hypocalcemia
Hyperphosphatemia
Anemia
Decreased urine output
Lack of improvement/worsening of azotemia
Pancreatitis
Sepsis
Poor prognostic indicators (cats)
• Significantly lower levels of:
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PCV
WBC
Albumin
LDH
Blood glucose
Body temperature
• Older patients
Diagnosis of AKI
• Risk, Injury, Failure, Loss, End-stage renal
disease (RIFLE)
• Acute Kidney Injury Network (AKIN)
• Veterinary Acute Kidney Injury Staging System
(VAKI)
• International Renal Interest Society (IRIS)
Three
stages
Two
outcomes
Risk
• Increase in SCr x 1.5
• GFR decrease > 25%
• UO < 0.5 ml/kg/hr x 6 hr
Injury
• Increase in SCr x 2.0
• GFR decrease > 50%
• UO < 0.5 ml/kg/hr x 12 hr
Failure
• Increase in SCr x 3.0
• GFR decrease > 75%
• UO < 0.3 ml/kg/hr x 24 hr
or anuria x 12 hr
Loss
ESRD
• Persistent ARF =
complete loss of
renal function x 4
weeks
• End-stage renal
disease
RIFLE in the clinic setting
• Severe dog fight presents to Urgent Care
▫ Stabilized, maintained on intravenous fluid
therapy
▫ Baseline serum creatinine (SCr) = 0.5 mg/dL
▫ SCr 48-hours later = 1.0 mg/dL
 Don’t over look this change!
 Yes, SCr is in the normal reference range, however…
▫ Injury category
Stage 1
• Creatinine increase from 150-199% from baseline
• Or creatinine increase of 0.3 mg/dL from baseline
Stage 2
• Creatinine increase from 200-299% from baseline
Stage 3
• Creatinine increase >300% from baseline
• Or absolute creatinine value > 4 mg/dL
VAKI in the clinic setting
• Hit by car, polytrauma
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Hypotensive/hypoxemic upon presentation
Stabilized in the ICU, hospital stay of 4 days
Baseline SCr = 0.6 mg/dL
Highest SCr value = 0.9 mg/dL
 Stage 1
Clinical relevance
• AKI staging in dogs
▫ Modified RIFLE criteria
 Mortality of dogs in the Injury/Failure category was
significantly higher than those in the Risk category
▫ Modified AKIN criteria (VAKI)
 Dogs meeting AKI criteria were less likely to survive
to discharge
▫ AKI staging criteria-Cowgill system
 Relationship exists between levels of AKI and
mortality at 30 and 90 days
Important point
• Small increases in SCr are clinically relevant
even when absolute values are within reference
intervals
New concepts
• Dogs appear to share similar cellular
mechanisms of AKI when looking
histopathologically
• Hydroxyethyl starches and AKI
▫ Significant concern in human medicine
Why might histopathology matter?
• Modification of patient therapy
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Discontinue potentially harmful medications
Cognizant fluid administration (type, amount)
Adjustment to anesthesia protocols
Other potential renal protective therapies
Initiation of extracorporeal therapies
Novel interventional therapy
• Owner education
▫ Prognosis
▫ Financial investment
Important findings in people
• Apoptosis may be an
important factor in
AKI secondary to
septic shock in people
• Does apoptosis
happen in dogs with
AKI?
Retrospective study
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Acute pancreatitis
Sepsis
Septic peritonitis
Multiple organ
dysfunction
syndrome (MODS)
▫ Trauma
▫ Hemoabdomen
▫ Disseminated
intravascular
coagulation (DIC)
▫ Non-renal
neoplasia
▫ Gastric dilitation
volvulus (GDV)
Medical records search (2002-2010)
Hospitalization in ICU for at least
48-hours
Normal SCr upon
admission
> 2 SCr
Increase in SCr during
hospitalization
Study population
Exclusion criteria:
-Previous renal disease
-Azotemic upon hospital
admission
-Post-renal causes of azotemia
No increase or <1.5 x in
SCr during
hospitalization
Control population
Histopathologic evaluation
• Assessing for the presence of apoptosis in the
study and control dogs
Results
• HA-AKI dogs exhibited more severe
histopathologic changes compared to dogs that
did not have significant increases in SCr, as
evident by increased numbers of apoptotic
bodies and TUNEL positive nuclei
Potential application?
• Understanding cellular mechanisms for
development of AKI may provide insight into the
prevention and treatment of this important
organ complication in critical illness
• Special staining may improve our scientific
understanding of the underlying apoptotic
pathways
Use of HES and AKI-what’s the
evidence?
• Information available is limited to human
medicine
• Important information to be aware of
• Early trials investigating HES solutions
▫ Lancet 2001 (first trial)
 Frequency of AKI, oliguria, peak SCr were
significantly higher in HES group
 HES use was an independent factor for AKI
Early trials investigating HES
• Based on results from Lancet 2001, additional
studies performed (variable results)
▫ SOAP study: HES use associated with higher need
for RRT
 Same finding not present after multivariable analysis
▫ CRYCO study: artificial colloids associated with
AKI in a dose-dependent manner
▫ VISEP study: trial stopped for safety reasons (high
rates of AKI and RRT)
Recent trials investigating HES
• Three recent trials looking at HES 130/0.4
▫ Theoretically a safer option because of lower MW
and MS
▫ CRYSTMAS study: no difference between AKIN
and RIFLE criteria or mortality up to 90 days
 Well designed, but deemed underpowered
▫ 6S trial: HES group had higher need for RRT and
had increased mortality at 90 days
▫ CHEST trial: higher incidence of AKI in crystalloid
group, higher need for RRT in HES group
Meta-analyses comparing HES and
crystalloids
• Cochrane Reviews
▫ 2011
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34 studies
Relative risk (RR) for AKI = 1.5
RR for RRT = 1.38
Increased risk of AKI should be considered when
weighing risk:benefit of HES for resuscitation
Meta-analyses comparing HES and
crystalloids
• Cochrane Reviews
▫ 2013
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42 studies
RR for AKI = 1.59
RR for RRT = 1.31
Conclusion: current evidence suggests that all HES
products increase the risk of AKI and RRT in all
patient populations
Meta-analyses comparing HES and
crystalloids
• JAMA Systematic Review and Meta-analysis
▫ 2012
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38 trials
RR for death = 1.07
RR for RRT = 1.32
Conclusion: clinical use of HES for acute volume
resuscitation is not warranted due to serious safety
concerns
Experimental studies
• Porcine kidney perfusion model
▫ Compared 10% HES 200/0.5, 6% HES 130/0.42
and LRS
▫ HES decreased urine output and chloride
clearance
▫ Increased beta-NAG (tubular injury biomarker)
▫ Osmotic nephrosis
▫ Macrophage infiltration, interstitial cell
proliferation
Experimental studies
• Rat models of sepsis
▫ One study compared 6% HES 130/0.4 and 0.9%
NaCL
 HES resulted in increased serum NGAL (renal injury
biomarker)
 Increased kidney injury scores based on
histopathologic analysis
Experimental studies
• Rat models of sepsis
▫ Another study compared two formulations of 6%
HES 130/0.42 vs crystalloid
 No independent effect of HES on inflammatory
mediator expression in the kidney
 No independent effect of HES on urine/serum NGAL
concentrations
Proposed mechanisms of injury
• Osmotic nephrosis
▫ Talked about most commonly
• Tubular plugging due to viscous urine
• Inflammation of the renal interstitium
Osmotic nephrosis
• Does not always result in proximal tubular
dysfunction
• Can develop and disappear without clinical signs
• AUS findings
▫ Non-specific
• Urinalysis
▫ Tubular proteinuria
▫ Vacuolated tubular cells
Osmotic nephrosis
• Autopsy results in people
▫ Large, pale kidneys
• Histopathology
▫ Focal or diffuse “clear-cell” transformation of
proximal tubular renal epithelial cells
▫ Tiny vesicles under apical cell membrane
▫ Fine vacuolization of the cytoplasm
How common is AKI 20 to HES in VM?
• We don’t know (yet)
• Some argue AKI secondary to HES doesn’t
happen in veterinary medicine
• Keep in mind the size of human trials
▫ Large veterinary trials will likely be indicated to
truly evaluate for AKI secondary to colloid use
• While dogs do have more alpha-amylase in their
plasma, we are not certain this protects them
against complications from HES use
Take home points
• AKI is an important disease process in critically
ill patients
• Complex physiology
• Small changes in SCr should not be overlooked
• Beginning to understand what may be
happening at the cellular level
• While not yet documented in dogs, the effects of
HES and AKI in human patients/experimental
models should be considered
Questions?
Ayla R. Preston, DVM, MS, Practice Limited to ECC
Small Animal Emergency and Critical Care
Four Seasons Veterinary Specialists
970-800-1106 (w)
draylab@gmail.com