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

2. Acute kidney Injury(AKI)
 Classifications
 Etiology
 Nutritional support
 Diuretic role
 Renal replacement therapy
 Specific type acute kidney injury

4. S-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

5. RIFLE classification
Acute Dialysis Quality Initiative

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

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

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

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

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

12. Acute renal failure: pre-renal/renal
LMW proteins
Brush border enzymes
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 >2
FE UA(%) <7 >15
FE lithium(%) <7 >20

13. Daily change in ARF
Noncatabolic Catabolic
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

14. BUN/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

16. Nutritional profile
Hyper- Mild Moderate Severe
catabolism (>N intake (>N intake (>N intake
+5) +5 ～ 10) +10)
Prot(g/Kg/D) 0.6-1.0 0.8-1.2 1.0-1.5
Energy 25 25-30 30-35
(Kcal/Kg/D)
Mortality 20% 60% >80%
Dialysis rare prn frequent
Clinical Drug- elective sepsis or
induced surgery emergency
surgery

17. Diuretic use for ARF
Total Favorable No Equivocal
=19 studies outcome improvement outcome
Renal 7 9 2
function(18)
Need for
dialysis(14) 7 5 2
Mortality
(15) 1 14

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

19. Initiation 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)

20. Dialysis 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

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

22. Hybrid 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

23. AVVH
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

24. SLEDD
 Slow 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)

25. CVVH 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

26. CVVHDF dose in ARF
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

27. Dialysis dosing in critically ill patients
with 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)

29. Outcomes 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)

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

32. AKI in Sepsis/SIRS: 11%
Yegenaga 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

34. AKI 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%)

35. Hepatorenal syndrome (1)
Seminar, 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

36. Hepato-renal syndrome (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

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

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

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

42. Aminoglycoside 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 (?)

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

45. Dye induced nephropathy
University 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

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

48. Cardio-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 ?

50. Acute phosphate nephropathy
Markowitz 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

52. Acute 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

54. Mechanical ventilator:
independent 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

55. Mechanical ventilator: renal failure
mechanisms
 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↓