Mechanisms and Management
in Acute Kidney Injury
Paul Stevens
Kent Kidney Care Centre
Father and Son
Chapter 55: Ischuria
Printed for Payne & Foss, Pall Mall, London
What I’m Not Going to Talk About
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Vasopressors
Dopamine agonists
Natriuretic peptides
Adenosine agonists
N-acetylcysteine
Loop diuretics and osmotic diuretics
Prophylactic dialysis/HF
What I Am Going to Talk About
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Conceptual models
Definition(s)
Why does it matter?
What’s important?
Adding insult to injury
UK AKI consensus
Could this happen in your hospital?
Avoiding AKI
Pathogenesis
Sudden causes
affecting
Called
Pre-renal
Renal Perfusion
Parenchymal
Structures
Urine output
Induce
GFR
Parenchymatous
(intrinsic)
Post-renal
AKI
Acute Kidney Injury
Prerenal AKI
Acute tubular
necrosis
Intrinsic AKI
Acute interstitial
nephritis
Acute GN
Postrenal AKI
Acute vascular
syndromes
Intratubular
obstruction
Glomerular Haemodynamics – Renal Hypoperfusion
Angiotensin II
Decreased afferent
blood flow
Decreased efferent
blood flow
Vasoconstriction
Vasodilatation
Prostaglandins
Decreased GFR
Hypoperfusion
(uncompensated)
Preserved GFR
Hypoperfusion
(compensated by PGE2 & AII)
Acute Kidney Injury Conceptual Model
Stages defined by
creatinine and
UOP are
surrogates
Complications
GFR
Normal
Increased
risk
Damage
Kidney
failure
 GFR
Antecedents
Intermediate Stage
AKI
Outcomes
Mehta et al . Critical Care 2007;11:R31
Death
Damage
Markers such as
NGAL, KIM-1 and
IL-18 are
surrogates
Definitions…
“That’s a new term the nephrologists came up
with, they’re still working on a definition for it”
RIFLE Criteria for AKI
GFR criteria
UOP criteria
Risk
SCr x1.5 or
GFR >25%
UOP < .5ml/kg/h
for 6 hrs
Injury
SCr x2 or GFR UOP < .5ml/kg/h
>50%
for 12 hrs
Failure
UOP < .5ml/kg/h
SCr x3 or GFR
for 24 hrs or
>75%
anuria for 12 hrs
Loss
Persistent ARF = complete loss of
kidney function > 4 weeks
ESRF
ESRF > 3 months
High
sensitivity
High
specificity
Bellomo et al. Crit Care 2004;8:R204-R212
Acute Kidney Injury Network Criteria
Stage
Creatinine Criteria
UOP Criteria
1
↑SCr ≥ 26.4 μmol/L or
↑SCr ≥ 150-200%
< 0.5 mL/kg/hr for > 6 hr
2
↑SCr > 200-300%
< 0.5 mL/kg/hr for >12 hr
3
↑ SCr >300% or
SCr ≥354 μmol/L + acute
↑ ≥44 μmol/L in ≤24hr or
RRT initiated
< 0.3 mL/kg/hr for 24 hr
or
anuria for 12 hr
48 hour time constraint
Mehta et al. Crit Care 2007;11:R31
KDIGO AKI Definition
• Acute kidney injury/impairment (AKI) is
defined as any of the following:
– Increase in SCr by >0.3 mg/dl (>26.4
µmol/L) within 48 hours, or
– Increase in SCr by >1.5-fold above
baseline which is known or presumed to
have occurred within 7 days, or
– Urine volume <0.5 ml/kg/h for 6 hours.
KDIGO AKI GL. Kidney inter., Suppl. 2012; 2: 1–138
KDIGO AKI Staging
Stage
Serum creatinine
Urine output
1
≥ 1.5-1.9 times baseline (7 days)
OR
26.5 µmol/L increase (48 hrs)
< 0.5 ml/kg/hr for
6-12 hrs
2
≥ 2.0-2.9 times baseline
< 0.5 ml/kg/hr for
≥12hrs
≥ 3.0 times baseline
OR
3
increase in creatinine to ≥ 354 µmol/L
OR
Renal replacement therapy
< 0.3 ml/kg/hr for
≥24hrs
OR
Anuria for ≥ 12hrs
KDIGO AKI Guideline. Kidney inter., Suppl. 2012; 2: 1–138
Why Does It Matter?
• AKI is commoner than
many realise
• Mortality from AKI
remains high
• AKI doubles hospital
length of stay
• AKI predicts
subsequent mortality
and CKD
• AKI is costly
What’s Important?
Baseline risks
Clinical conditions
Drugs
Advanced age
Sepsis
Contrast media
Diabetes
Hypotension/Shock
Antibiotics
CKD
Volume depletion
Chemotherapy
Heart failure
Rhabdomyolysis
NSAIDs
Liver failure
Cardiac/vasc surg
ACEI/ARB
Male gender
Non-renal solid organ Tx
Race/genetic
Mechanical ventilation
Low albumin
Abdominal compartment
syndrome
ADQI 4th Consensus Conference
Arterial disease
Key Assessments: All Patients
All 3 Key Assessments
2 of 3 Key Assessments
1 of 3 Key Assessments
No Key Assessments
Stevens et al, QJ Med 2001;94:553-560
Factors Associated with Stage 3 AKI
N = 288 of which 163 community acquired and 125 hospital acquired
Volume
depletion &/or
hypotension
Drug related
Sepsis
Obstruction
Stevens et al, QJ Med 2001;94:553-560
NCEPOD Key Findings
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Only 50% of AKI care considered good
Poor assessment of risk factors
Delay in recognition of AKI post-admission in 43%
Poor recognition of acute illness, hypovolaemia
and sepsis
• 33% of patients had inadequate investigations
• 29% had inadequacies in clinical management
• Complications missed (13%), avoidable (17%) or
badly managed (22%)
UK AKI Consensus 2012:
Biomarkers, e-Alerts & Fluids
Authors/members of Consensus Panel: Feehally J (Co-Chair); Gilmore I (Co-Chair); Barasi S; Bosomworth M; Christie B;
Davies A; Dhesi J; Dowdle R; Gibbins C; Gonzalez I; Harding S; Lamont D; Murphy G; Ostermann M; Parr J; Stevens PE
UK AKI Consensus: Apple Pie Stuff
• Improved training and education
• Early recognition of AKI
• All non-elective admissions require
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assessment of risk factors for AKI
assessment of volume status
urinalysis
medicines review, ACEi/ARB, NSAID should be
withheld pending senior review within 12 hours
– baseline SCr and electrolytes repeated within 24 h
• Agreed nephrology referral criteria
http://www.rcpe.ac.uk/clinical-standards/standards/uk-consensus-statement-onmanagement-of-acute-kidney-injury-nov-2012.pdf
UK AKI Consensus: Specifics
• Fluid therapy should be guided by repeated
evaluation of volume status. A balanced salt
solution should be the usual fluid for volume
replacement
• Identification of AKI in both primary and
secondary care should be facilitated through
introduction of e-alert systems
• It is premature to recommend the use of novel
biomarkers of AKI in current clinical practice
Fluid Prescribing: Lessons Not Learned
• NCEPOD Extremes of Age (1999)
– Fluid management in the elderly is often poor; it should be
accorded the same status as drug prescription
• Scottish Audit of Surgical Mortality (2009)
– Fluid balance in the surgical patient remains problematic,
often managed by relatively junior staff and continuing
education and use of appropriate guidance is to be
encouraged
• NICE IV fluid therapy in adults in hospital (2013)
– Errors in prescribing, leading to insufficient or excessive
provision of IV fluids or electrolytes, are common and have
adverse effects on patient morbidity and mortality
AKI and Volume Loading
• Korean War
– Incidence of dialysis requiring AKI 1:200
• Vietnam War
– Incidence of dialysis requiring AKI 1:600
• Colloids
– Albumin
– Gelatins
– Starches
Or
• Crystalloids
– 0.9% saline
– Dextrose
– Balanced solutions
Abnormal Saline
THE ABUSE OF NORMAL SALT SOLUTION
Evans GH. JAMA 1911;LVII(27):2126-2127
“under certain circumstances saline solutions are productive of great harm
to the tissues of the body, and are even capable of producing death”
ELECTROLYTE SOLUTION APPROXIMATING PLASMA
CONCENTRATIONS
Fox CL, Winfield JM, Slobody LB, Swindler CM, Lattimer JK. JAMA
1952;148(10):827-833
“retention of chloride exceeded the retention of sodium in all experiments
with sodium chloride solutions and emphasize the disadvantage of using
chloride in replacement solutions in concentrations that are greater than
the normal concentration of chloride in plasma”
Crystalloid Solution Characteristics
Solution
Electrolyte Content
(mmol/l)
Osmolality
(mOsm/kg)
pH
0.9% NaCl
Na+ 154
Cl- 154
308
5.0
Dextrose (4%)
Saline (0.18%)
Na+ 31
Cl- 31
286
4.5
Nil
Nil
280
4.0
Na+ 131
K+
5
Ca2+ 2
Cl111
HCO3- 29†
276
7.0
Na+ 140
K+
5
Mg2+ 1.5
Cl98
HCO3- 29*
294.5
5.0
5% Dextrose
Hartmann’s
solution
Plasmalyte®148
Saline vs. Hartmans in Healthy Subjects
• Double blind crossover study in 10 healthy male
volunteers
• 2 L of 0.9% saline or Hartmann's solution infused over
60 min
• Subjects not allowed to eat or drink
• Body weight and blood tests hourly for 6 h
• Subjects voided their bladders as the need arose and, in
all cases, at the end of 6 h
• No significant difference in baseline parameters prior to
infusions
Reid et al. Clinical Science 2003;104:17–24
• 56% of the infused saline was
retained, compared with 30% of the
Hartmann's solution
• time to micturition less after
Hartmann's than after saline
(median: 70 cf. 185 min; p = 0.008)
Reid et al. Clinical Science 2003;104:17–24
Saline vs. Plasmalyte® in Healthy Subjects
• Randomized, double-blind, cross-over study of 2 L of 0.9%
saline or Plasma-lyte®148 solution infused over 60 min in
12 male volunteers
• MRI measurements at t = 90 min to assess renal cortical
tissue perfusion and renal artery blood flow velocity
Chowdhury et al. Ann Surg 2012;256:18–24
0.9% saline cf. Plasmalyte in Abdominal Surgery
• Observational study of adult patients undergoing major
open abdominal surgery
– 0.9% saline (30,994 patients) or a balanced crystalloid solution
(926 patients)
• Outcomes
– in-hospital mortality 5.6% (saline) vs. 2.9% (balanced)
– ≥1 major complications 33.7% (saline) vs. 23% (balanced)
• Treatment with balanced fluid was associated with less
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–
–
–
infection (P = 0.006)
renal failure requiring dialysis (P < 0.001)
blood transfusion (P < 0.001)
electrolyte (P = 0.046) and acid-base disturbance (P < 0.001),
and intervention (P = 0.02)
Shaw et al. Ann Surg 2012;255:821–829
From: Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration
Strategy and Kidney Injury in Critically Ill Adults
Yunos NM et al. JAMA. 2012;308(15):1566-1572. doi:10.1001/jama.2012.13356
• Chloride rich (0.9% saline, 4% succinylated gelatin solution, or 4%
albumin solution) versus chloride poor (Hartmann’s, Plasma-Lyte 148 or
chloride-poor 20% albumin)
• Chloride administration decreased by 144 504 mmol (from 694 to 496
mmol/patient) from control to intervention periods
Fluid Balance Lesson for Surgeons
• “The body is not analogous to a tank
into which water can be forced until it
finally bursts out through the kidneys”
Lattimer JK: A Plan for the Management of
Anuria. J. Urology, 54: 312-317, 1945
AKI and Volume Responsiveness
Adapted from Himmelfarb et al Clin J Am Soc Nephrol 2008:3;962-967
Acute Kidney Injury and Sepsis
AKI occurs in
– 19% culture positive in
moderate sepsis
– 23% culture positive in
severe sepsis
– 51% culture positive in
septic shock
70% mortality in sepsis
and AKI combined
Rangel-Frausto et al. JAMA 1995;273:117-123
Schrier & Wang NEJM 2004;351:159-69
Assessment and Monitoring:
Physiological Observations
• Initial assessment should include at least:
– heart rate
– respiratory rate
– systolic blood pressure
– level of consciousness
– oxygen saturation
– temperature.
Acutely ill patients in hospital: NICE clinical guideline 50
AKI in East Kent: Initial Assessments
All AKI
n=288
Sepsis & AKI
n=74
Respiratory rate
29%
38%
Oxygen status
30%
49%
Blood culture
42%
66%
MSU
57%
73%
CRP
18%
31%
Stevens et al, QJ Med 2001;94:553-560
Assessment Can Be Influenced
Could This Happen in Your Hospital?
• 37 year old man, depressed
• 1 litre of Brandy, 24 paracetamol, 12
Nurofen plus at c. 18.00 hrs
• Vomited, fell asleep against a radiator
and woke up the following morning
• Left leg was uncomfortable on waking
and swollen
Could This Happen in Your Hospital?
• Presented to A&E 10.30 a.m. seen by
Orthopaedic SHO, admitted, NBM in
case of theatre, Voltarol analgesia
• Muddy brown urine (once)
• Reviewed at 18.40 hrs
– Tachycardic, lying BP of 130/80
– Unable to move his left leg, left KJ & AJ
were absent
– Medical SHO called
Could This Happen in Your Hospital?
• Treated with Parvolex, bloods sent
• Results
– Na 138, K 5.2, Urea 19.1, Creatinine 280, Alb 40,
AST 1738. Clotting was normal, FBC showed
WCC 20.9 (19.3N), Hb 17.8, Plt 247. Paracetamol
and aspirin levels were below toxic levels
• Medical registrar reviewed him at 23.15 and
noted severe oedema in the left thigh,
sensory and motor loss in the left leg and
muscle fasciculation
Avoiding Acute Kidney Injury
1.
2.
3.
4.
5.
6.
Recognise and assess the patient at risk
Avoid nephrotoxic agents
Maintain effective circulatory volume
Recognise and treat hypoxia
Treat infection, avoid nosocomial infection
Pharmacological manipulation to maintain RBF,
perfusion pressure and GFR
Per Ardua Ad Urinam
Acknowledgements:
• Air Commodore David
Rainford
• Dr Chris Farmer
• Jean Irving
• Helen Hobbs
• Toby Wheeler
• Dr Hannah Kilbride
• Dr Michael Bedford