A New Perspective on AcuteA New Perspective on Acute
Kidney InjuryKidney Injury
by Steve Chenby Steve Chen
Director of Nephrology,
Shin-Chu Branch of Taipei Veterans General Hospital

Temporal trends in the hospital-based & population-based
incidence of AKI: a growing problem

Acute kidney Injury(AKI)Acute kidney Injury(AKI)
Definition and Stage
Etiology
KDIGO-AKI 2012 Guideline
Nutritional support
Diuretic role
Renal Replacement Therapy
Outcomes
Specific type acute kidney injury

S-Cr based definitions of AKIS-Cr based definitions of AKI
Parameter Definitions
Acute Kidney Injury Network Stage 1: ≧0.3 mg/dl increase or 50%
increase
(AKIN) over baseline
within 48Hr
Stage 2:≧100% increase over
baseline
Stage 3: ≧200% increase or 0.5mg/dl
increase
to at least 4.0 mg/dl
Acute Dialysis Quality Initiative RIFLE(R) ≧50%
increase over baseline
RIFLE(I) ≧100%
increase over baseline
RIFLE(F) ≧200%
increase over baseline or

Cr kinetics based definition of AKICr kinetics based definition of AKI
SS Waikar: JASN 2009( Harvard Medical School, Boston)

RIFLE stageRIFLE stage
Acute Dialysis Quality Initiative

RIFLE and mortality in AKIRIFLE and mortality in AKI
Z Ricci et al: KI 73: 538-546, 2008 (Italy)Z Ricci et al: KI 73: 538-546, 2008 (Italy)

AKI: long-term mortality(>3M)
1.2
1.25
1.3
1.35
1.4
1.45
1.5
1.55
1.6
AKIN-I AKIN-II AKIN-III All
P<0.001
N=864933
Lafrance et al: JASN 21: 345-352, 2010

AKI-induced distant organ effectsAKI-induced distant organ effects
KC: karatinocyte-derived chemokine
GFAP: glial fibrillary acidic protein
VP: vascular permeability

Acute renal failure: etiologyAcute renal failure: etiology
type Clinical Conditions
Pre-renal
(40 ～
80%)
Heart failure
Hypotention
Volume loss/sequestration
---
---
---
Renal
(10 ～
30%)
Vascular disorders
GN
Interstitial disorders
Tubular necrosis
Vasculitis
---
---
Ischemia/Toxin
Post-renal
(5 ～ 15%)
Intra-renal
Extra-renal
Crystal/protein
---

Hospital-acquired AKIHospital-acquired AKI
Nash et al, AJKD 39: 930-936, 2002Nash et al, AJKD 39: 930-936, 2002
Causes Episodes Mortality
↓Renal perfusion
Medications
Contrast media
Post-operative
Sepsis
S/P liver transplant
S/P heart transplant
Obstruction
147
61
43
35
25
14
8
7
13.6%
15%
14%
2.8%
76%
28.6%
37.5%
28.6%

Acute renal failure:Acute renal failure: pre-renal/renalpre-renal/renal
pre-renal renal
U/A Hyaline casts abnormal
S.G. >1.020 ～ 1.010
Uosm(mOsm/Kg) >500 <300
Una (meq/L) <20 >40
FE Na (%) <1 >1
FE UA(%) <7 >15
FE lithium(%) <7 >20
LMW proteins
Brush border enzymes

Daily change in ARFDaily change in ARF
BUN(mg/dl) 10-20 >30
Cr <1.5 >1.5
K(meq/L) <0.5 >0.5
HCO3 <2 >2
Pi(mg/dl) <1 >1
Noncatabolic
Catabolic

BUN/Cr >15BUN/Cr >15
 Increased urea formation:
High protein intake
Increased intestinal absorption of urea/NH4- GI
bleeding, ureteral diversion
Catabolic state- fever, tissue necrosis, steroid
use, tetracycline use, sepsis
 Decreased urea elimination:
Volume depletion
Heart failure
Obstructive nephropathy

KDIGO:Grading of evidence
Level 1 ‘We recommend Most patients should receive the recommended
course of action
Level 2 ‘We suggest’
Grade A high quality
Grade B good quality
Grade C moderate quality
Grade D poor quality
Different choices will be appropriate for different
patients. Each patient needs help to arrive at a
management decision consistent with her or his
values and preferences
Evidence obtained from at least one properly
designed randomized controlled trial (≧ 1 RCT)
Evidence obtained from well-designed controlled
trials without randomization (CT)
Evidence obtained from well-designed cohort or
case-control analytic studies, preferably from more
than one center or research group
Evidence obtained from multiple time series with
or without the intervention and uncontrolled trials

PREVENTION AND TREATMENT OF
AKI
3.1.1
In the absence of hemorrhagic shock, we
suggest using isotonic crystalloids rather
than colloids (albumin or starches) as initial
management for expansion of intravascular
volume in patients at risk for AKI or with
AKI. (2B)

3.1.2
We recommend the use of vasopressors in
conjunction with fluids in patients with
vasomotor shock with AKI or at risk for
AKI. (2C)

3.1.3
We suggest using protocol-based
management of hemodynamic and
oxygenation parameters to prevent
development or worsening of AKI in high-
risk patients in the perioperative setting
(2C) or in patients with septic shock (2C).
The best-known study is the Early Goal
Directed Therapy

3.3.1
In critically ill patients, we suggest
insulin therapy targeting plasma glucose
of 110–149mg/d (6.1–8.3mmol/l). (2C)

3.3.2
We suggest achieving a total energy intake
of 20–30kcal/kg/D in patients with any
stage AKI. (2C)

3.3.3
We suggest avoiding restriction of
protein intake with the aim of preventing
or delaying initiation of RRT. (2D)

3.3.4
We suggest administering 0.8–1.0 g/kg /D
of protein in non-catabolic AKI patients
without need for dialysis (2D)
1.0–1.5 g/kg/D in patients with AKI on
RRT (2D)
Up to a maximum of 1.7 g/kg/D
inpatients on continuous renal
replacement therapy (CRRT) and in
hyper-catabolic patients. (2D)

3.3.5
We suggest providing nutrition
preferentially via the enteral route in
patients with AKI. (2C)

Guideline 3.4: The use of
diuretics in AKI
3.4.1: We recommend not using diuretics to
prevent AKI. (1B)
3.4.2: We suggest not using diuretics to
treat AKI, except in the management of
volume overload. (2C)

Guideline 3.5: Vasodilator
therapy
3.5.1: We recommend not using low-dose
dopamine to prevent or treat AKI. (1A)
3.5.2: We suggest not using fenoldopam to
prevent or treat AKI. (2C)
3.5.3: We suggest not using atrial
natriuretic peptide (ANP) to prevent (2C) or
treat (2B) AKI.

Guideline 3.6: Growth factor
intervention
3.6.1
We recommend not using recombinant
human(rh)IGF-1 to prevent or treat AKI.
(1B)

Guideline 3.7: Adenosine
receptor antagonists
3.7.1
We suggest that a single dose of
theophylline maybe given in neonates with
severe perinatal asphyxia who are at high
risk of AKI. (2B)

Guideline 3.8: Prevention of
aminoglycoside-related AKI
3.8.1: We suggest not using aminoglycosides for
the treatment of infections unless no suitable,
less nephrotoxic, therapeutic alternatives are
available. (2A)
3.8.2: We suggest that in patients with normal
kidney function in steady state, aminoglycosides
are administered as a single dose daily rather
than as multiple-dose daily treatment regimens.
(2B)

Guideline 3.8: Prevention of
aminoglycoside-related AKI
3.8.3: We recommend monitoring
aminoglycoside drug levels when treatment
with multiple daily dosing is used for more
than 24h. (IA)
3.8.4: We suggest monitoring
aminoglycoside drug levels when treatment
with single-daily dosing is used for more
than 48h. (2C)

Guideline 3.9: Other methods of
prevention of AKI in the critically ill
3.9.1: We suggest off-pump CABG surgery not
be selected solely for the purpose of reducing
perioperative AKI or the need for RRT. (2C)
3.9.2: We suggest not using NAC to prevent AKI
in critically ill patients with hypotension. (2D)
3.9.3: We recommend not using oral or IV NAC
for prevention of postsurgical AKI. (1A)

Initiation of dialysisInitiation of dialysis
Kt/V <2.0/week; GFR<10.5,
Kcr<14.5,Kurea<7 ml/min per 1.73m2
Symptoms(progressive or unexplained)
Anorexia, Nausea, Vomiting
Fatigue
Sleep disturbance
Nutritional status
Decreasing edema-free BW
Hypo-albuminemia
Low SGA( 5)≦

Dialysis for ARFDialysis for ARF
BUN>100mg/dl, Cr>10mg/dl
Hyperkalemia(>6.5meq/L,intractable)
Severe metabolic acidosis(pH<7.1)
Dysnatremia(Na>160 or <110meq/L)
Uremic symptoms
Uremic encephalopathy, pericarditis,
bleeding, gastroenteritis, neuromuscular p.
Organ edema,especially lung edema
Oliguria
Overdose with dialysable toxin
Hyperthermia

Renal replacement therapyRenal replacement therapy
IHD: intermittent HD
CVVH/CVVHDF: continuous veno-venous
hemofiltration/continuous veno-venous
hemo-diafiltration
Hybrid RRT

Hybrid RRT: EDD-fHybrid RRT: EDD-f
Extended Daily Diafiltration: EDD-f
The future in critical care nephrology
Sustained Low Efficiency Daily
Diafiltration: SLEDD-f
AVVH: Accelerated VenoVenous
Hemofiltration

SLEDDSLEDD
Sustained Low Efficient Daily Dialysis
Low Qb and low Qd: 200ml/min≦
Filtration rate: 25-30 ml/min
Session duration: 6 ～ 12Hr/D
Advantages of both CRRT and IHD
Kt/V targeting 1.2 ～ 1.4 per session with
a frequency of 6 times a week (Intensive);
TIW(less intensive)

AVVHAVVH
Casey et al: AJKD 2008(Ruch University Medical Center, Chicago)Casey et al: AJKD 2008(Ruch University Medical Center, Chicago)
Accelerated VenoVenous Hemofiltration
Low Qb : 350 ～ 400 ml/min
Net fluid removal rate: 2.5L/Treatment
Replacement fluid in pre-dilution mode:36L
No anticoagulation
Session duration: 9 Hr/D
Advantages of both CRRT and IHD

Outcomes after acute kidney injuryOutcomes after acute kidney injury
Study design: Systemic review and meta-analysis
48 studies/N=47017
15 studies reported long-term data for patients without AKI
Selection criteria:
MEDLINE and EMBASE from 1985 to October 2007: hospital case
Excluded for F-U ≦ 6M
Results:
1> Incidence rate of mortality: 2.59 X (rate ratio)
8.9/100 P-Y in survivors of AKI
and 4.3/100 P-Y in survivors without
2> Mortality risk in 6 of 6 studies: 1.6~ 3.9 by adjusted RR
3> Myocardial infarct in 2R of 2 studies: 2.05 by RR
4> Incidence rate of CKD: 7.8events/100 P-Y
5> Rate of ESRD: 4.9events/100 P-Y
SG Coca et al: AJKD 53: 961-973, 2009 (Yale University)

Causes of AKI: exposures &Causes of AKI: exposures &
susceptibilities forsusceptibilities for
non-specific AKInon-specific AKI
Exposures Susceptibilities
Sepsis
Critical illness
Circulatory shock
Burns
Trauma
Cardiac surgery
Major non-cardiac surgery
Nephrotoxic drugs
Radio-contrast agents
Poisonous plants and animals
Dehydration or volume
depletion
Advanced age
Female
Black race
CKD
Chronic diseases(heart, lung,
liver)
DM
Cancer

AKI in Sepsis/SIRS: 11%AKI in Sepsis/SIRS: 11%
Yegenaga et al, AJKD 43: 817-824, 2004Yegenaga et al, AJKD 43: 817-824, 2004
Age↑
S-Cr > 2.0 mg/dl
S-bilirubin > 1.5 mg/dl
CVP ↑: pulmonary/cardiac involvement
Risk factors

AKI in acute liver failureAKI in acute liver failure
Incidence: 50%
Precipitants: ↓IVF , ↓ CO, Hypoxia, ↓SVR;
Sepsis, nephro-toxins; IIAP
Prevention: timely elective liver
transplantation(LT) for non-acute hepatic
failure
LT: ↓ mortality( from 80% to 40%)

Hepatorenal syndromeHepatorenal syndrome (1)(1)
Seminar, Lancet 362: 1819-27, 2003Seminar, Lancet 362: 1819-27, 2003
Incidence: 40% over 5 years in cirrhotic
ascites
Renal failure: progressive oliguria
Hyponatremia, dilutional: often
Hyperkalemia, moderate: common
Severe metabolic acidosis→ infection
Hemodynamic instability →infection
Major cause of death: severe bacterial
infection

Hepato-renal syndromeHepato-renal syndrome (2)(2)
Chronic/ acute liver disease with advanced
hepatic failure&portal HTN
Low GFR: S-Cr > 1.5mg/dl / GFR <
40ml/min
R/O shock, infection, toxin, &fluid loss
No sustained improvement in renal
function: after diuretic withdrawal/IV NS
1500cc
Proteinuria < 500mg/D; negative sonogram
IV albumin: 1.5G/Kg if SBP; 1G/Kg at D3
↓Mortality and ↓renal impairment

Hepato-renal syndromeHepato-renal syndrome (3)(3)
Urine volume < 500ml/D
Urine Na < 10meq/L
Urine osmolality > plasma osmolality
Serum Na < 130meq/L
Urine RBC < 50/HPF

Hepatorenal syndromeHepatorenal syndrome (4)(4)
Seminar, Lancet 362: 1819-27, 2003Seminar, Lancet 362: 1819-27, 2003
Type I Type II
Definition ↑100% S-Cr in < 2
W: →>2.5 mg/dl
Other
Clinical GFR < 20mL/min
S-Cr, av : 3.1 mg/dl
Severe renal failure
GFR >20 mL/min
S-Cr, av : 1.6mg/dl
Recurrent ascites
Survival at
4M
<0.1 <0.6

Mortality of AKI after first acute strokeMortality of AKI after first acute stroke
Tsagalis G et al: Clinical J Am Soc Nephrology 2009( University of Athens, Greece)Tsagalis G et al: Clinical J Am Soc Nephrology 2009( University of Athens, Greece)

Aminoglycoside nephrotoxicityAminoglycoside nephrotoxicity
 GM.Tobramycin>Amikacin>Netrilmycin
 Risk factors:
pre-existing renal disease
advanced age
dose&duration
concurrent use of nephrotoxic agents
sepsis
hepatic failure
volume depletion; salt-restriction
metabolic
acidosis,hypokalemia,hypomagnesemia (?)

Contrast-agent induced AKIContrast-agent induced AKI
C.M. Sandler, NEJM 348: 551-553, 2003C.M. Sandler, NEJM 348: 551-553, 2003
Ionic
monomers:
Sodium
Diatrizoate
Nonionic
monomers: Iohexol
Nonionic
dimers:
Iodixanol
Osmole
(mOsm/Kg)
1500 ～
1800
600 ～ 850 iso-osmolar
Clinical
Nephrotoxicity
indications:
1
1
1
Safer : 6X
Expensive:25X
≤1
DM with RF?
<1
DM with RF
S-cr 1.5 ～
3.5

Risk factors for contrast nephropathy
Iodinated contrast
risk factors
Dose
Intra-arterial administration
Osmolality
Charge
Repeated administration<72 h
Procedure risk factors Interventional versus diagnostic
Blood loss
Hypotension
Patient factors Hypovolemia
Pre-existing chronic kidney disease
Comorbidity (diabetes, heart failure, myeloma,
peripheral vascular disease, cerebrovascular
disease)
Concomitant drugs (NSAIDs, calcineurin
inhibitors, aminoglycosides, cisplatin,
amphotericin B)

Risk score for developing AKI due to
contrast nephropathy
Risk factors Points awarded
Hypotension
Intra-aortic balloon pump
Chronic heart failure
Age >75 years
Anemia
Diabetes
Iodinated contrast volume
Serum creatinine >1.5mg/dl
or eGFR<60ml/min
Score
5
6-10
11-16
>16
5
5
5
4
3
3
1/100ml
4
2 if eGFR 40–60ml/min
4 if eGFR 20–40ml/min
6 if eGFR<20ml/min
7.5% risk CN-AKI 0.04% risk dialysis
14% risk CN-AKI 0.12% risk dialysis
26.1% risk CN-AKI 1.09% risk dialysis
57.3% risk CN-AKI 21.6% risk dialysis

Dye induced nephropathyDye induced nephropathy
University of Milan, NEJM 349: 1333-1340,2003University of Milan, NEJM 349: 1333-1340,2003
 Indications:
S-Cr > 2.0 mg/dl ( C-Cr>4 mg/dl with greatest positive effect
of long-term survival)
multiple interventions
 Hemo-filtration:
fluid replacement rate 1000ml/Hr
saline hydration 1ml/Kg/Hr
 Time: 4-8Hr before ~18-24Hr after
 In hospital mortality: 2% vs 14% p=0.02
Cumulative 1-Y mortality 10% vs 30% p=0.01

Dye induced nephropathyDye induced nephropathy
University of Milan, NEJM 349: 1333-1340,2003University of Milan, NEJM 349: 1333-1340,2003
0
0.5
1
1.5
2
2.5
3
3.5
D0 D1 D2 D4 Dis
S-Cr, control
Hemofiltration

Cardio-renal syndromeCardio-renal syndrome
 Definition:
Baseline renal function: S-Cr > 1.3 mg/dl and
estimated C-Cr 60 ml/min; Worsening renal≦
function( 0.3mg/dl)≧
 Risk factors: prior CHF/older/DM/HTN/Renal
dysfunction
 LVEF 40%: 37≧ ～ 55% not characterized by
low-output state but by fluid retention
 ACEI/ARB: empirical
 Effective diuresis: ? Maybe in some cases
 Natriuretic peptides: Nesiritide ?

Acute phosphate nephropathyAcute phosphate nephropathy
Markowitz et al: JASN 2007 Columbia UniversityMarkowitz et al: JASN 2007 Columbia University
 Definition: 1.16 ～ 6.3%
Baseline renal function: S-Cr > 1.3 mg/dl and
estimated C-Cr 60 ml/min; Worsening renal≦
function( 0.5≧ ～ 1.0mg/dl) 6 ～ 12M after colonoscopy
 Risk factors: Female/older/CHF/Diuretic use/ACEI use
 Hydration: 72 ounces of clear liquids for 30≧ ～ 45 ml
OSP
Avoidance of anesthesia regimens: no oral intake for 4-
6 Hrs
Alternative agents in female: PEG (polyethylene glycol)
Dose reduction or avoidance in the elderly/risk factors

Acute renal & hepatic failureAcute renal & hepatic failure
Infectious: Leptospirosis; Hantaan vitus,
Reyes syndrome
Toxic: Acetaminophen, methoxyflurane,
CCl4, tetracycline in pregnancy
Collagen vascular disease: SLE, PAN
Neoplastic: RCC, metastatic disease
Genetic: PCKD, sickle cell disease
Amyloidosis

Mechanical ventilatorMechanical ventilator::
independent predictor of acute kidney injuryindependent predictor of acute kidney injury
PEEP < 6: OR=2.89 ; PEEP>6: OR=20.7
Vivino et al, Intensive Care Med 24: 808-14, 1998
Incidence :
PEEP>6: 73%
PEEP<6: 36%
Venturi mask: 17%
Vivino et al, Intensive Care Med 24: 808-14, 1998
Predictors of mortality/ dialysis in PTS with
ATN Chertow et al, JASN 9: 692-98, 1998

Mechanical ventilatorMechanical ventilator:: renal failurerenal failure
mechanismsmechanisms
 Cardiovascular change:
volume status; cardiac status; pulmonary status
 Redistribution of intra-renal blood flow:
ET-B→NO ↑and PG↑
 Hormone pathways:
ADH↑: barorecetor-mediated; non-baroreceptor-mediated
Renin↑: β-mediated
sympathetic tone↑;distal Na delivery↓
ANP↓

Diuretic status on mortalityDiuretic status on mortality
Urine
volume(cc/D)
Mortality
(%)
OR for death
≦50 80 1.95
50 ～ 400 76 1.76
400 ～ 1000 43 1
1000 ～ 2000 22 0.5
≧2000 13 0.3

CVVH dose in ARFCVVH dose in ARF
 Prospective randomized trial: N= 425 in ICU ARF
 CVVH with post-dilution; Qb 145 ～ 207 ml/min
 Gr I: Uf=20ml/H/Kg Gr
II: Uf=35ml/H/Kg Gr
III: Uf=45ml/H/Kg
 Survival at 15 days after CVVH: (adjusting)
Gr I: 41% < Gr II: 57% (p=0.0007) ∞ Gr III:
58% (p=0.0013)
 Renal recovery of survivors at D15:
Gr I: 95%; Gr II: 92%; Gr III: 90%
 Early start in all group survivors
Ronco et al, Lancet 355: 26-30, 2000

CVVHDF dose in ARFCVVHDF dose in ARF
Tolwani et al: JASN 2008( University of Alabama at Birmingham)Tolwani et al: JASN 2008( University of Alabama at Birmingham)
 Prospective randomized trial: N= 200 in ICU ARF
 CVVHDF with pre-filter replacement fluid; Qb
100 ～ 150 ml/min
 Survival at ICU discharge or 30 days
Gr I: 56%; Gr II: 49% (p=0.32)
 Renal recovery in survivors:
Gr I: 80%; Gr II: 69% (p=0.29)
 Gr I: Effluent rate=20ml/H/Kg
Gr II: Effluent rate=35ml/H/Kg
 A difference in survival or renal recover: not
detected

Dialysis dosing in critically ill patientsDialysis dosing in critically ill patients
with AKIwith AKI
 Multicenter randomized trial: enrollment of 1164
to achieve a 10% difference in morality rate with
statical power of 90% with P value of 0.05
 Hemo-dynamically stable: IHD
 Unstable: CVVHDF(total effluent rate: 35 or 20
ml/Kg/Hr) or SLED( 6 or 3 times per week)
 Primary end point: 60-day all cause mortality
 Mortality: 53.6% in intensive; 51.5% in less-
intensive
 Renal/Non renal organ recovery rate: similar
Palevsky PM et al NEJM 359: 7-20, 2008 (VA/NIH Acute renal failure Trial Network)