A New Perspective on Acute A New Perspective on Acute Kidney Injury Kidney Injury

by Steve Chenby Steve Chen

Director of Nephrology, Shin-Chu Branch of Taipei Veterans General Hospital

Acute kidney Injury(AKI)Acute kidney Injury(AKI)

Classifications EtiologyNutritional supportDiuretic role Renal replacement therapy Specific type acute kidney injury

S-Cr based definitions of AKIS-Cr based definitions of AKIParameter 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 0.5 mg/dl increase to at least 4.0 mg/dl

Contrast nephropathy ≧0.5 mg/dl increase or 25% increase over baseline Hou et al ≧0.5 mg/dl increase if S-Cr ≦ 1.9 mg/dl ≧1.0 mg/dl increase if S-Cr 2.0 to 4.9 mg/dl ≧1.5 mg/dl increase if S-Cr > 5 mg/dl

RIFLE classificationRIFLE classification

Acute Dialysis Quality Initiative

Cr kinetics based definition of AKI Cr kinetics based definition of AKI

SS Waikar: JASN 2009( Harvard Medical School, Boston)

RIFLE and mortality in AKIRIFLE and mortality in AKIZ 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 chemokineGFAP: glial fibrillary acidic proteinVP: 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

---

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 >2

FE UA(%) <7 >15

FE lithium(%) <7 >20

LMW proteinsBrush 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

Nutritional profileNutritional profile

Hyper-catabolism

Mild(>N intake

+5)

Moderate (>N intake +5 ～ 10)

Severe (>N intake

+10)

Prot(g/Kg/D)

Energy (Kcal/Kg/D)

Mortality

Dialysis

Clinical

0.6-1.0

25

20%

rare

Drug-induced

0.8-1.2

25-30

60%

prn

elective surgery

1.0-1.5

30-35

>80%

frequent

sepsis or emergency surgery

Diuretic use for ARFDiuretic use for ARF

Total =19 studies

Favorable

outcome

No improvement

Equivocal

outcome

Renal function(18)

Need for dialysis(14)

Mortality (15)

7

7

1

9

5

14

2

2

Diuretic status on mortality Diuretic 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

Initiation of dialysisInitiation of dialysisKt/V <2.0/week; GFR<10.5,

Kcr<14.5,Kurea<7 ml/min per 1.73m2Symptoms(progressive or unexplained)

Anorexia, Nausea, Vomiting Fatigue Sleep disturbance

Nutritional status Decreasing edema-free BW Hypo-albuminemia Low SGA( 5) ≦

Dialysis for ARFDialysis for ARFBUN>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 HDCVVH/CVVHDF: continuous veno-venous

hemofiltration/continuous veno-venous hemo-diafiltration

Hybrid RRT

Hybrid RRT: EDD-fHybrid RRT: EDD-f

Extended Daily Diafiltration: EDD-fThe future in critical care nephrologySustained Low Efficiency Daily

Diafiltration: SLEDD-fAVVH: Accelerated VenoVenous

Hemofiltration

AVVHAVVHCasey et al: AJKD 2008(Ruch University Medical Center, Chicago)Casey et al: AJKD 2008(Ruch University Medical Center, Chicago) Accelerated VenoVenous HemofiltrationLow Qb : 350 ～ 400 ml/minNet 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

SLEDDSLEDD

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 IHDKt/V targeting 1.2 ～ 1.4 per session with

a frequency of 6 times a week (Intensive); TIW(less intensive)

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 ARFTolwani 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 patients Dialysis 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)

Outcomes after acute kidney injury Outcomes after acute kidney injury

Study design: Systemic review and meta-analysis 48 studies/N=4701715 studies reported long-term data for patients without AKI

Selection criteria: MEDLINE and EMBASE from 1985 to October 2007: hospital caseExcluded 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 RR3> Myocardial infarct in 2R of 2 studies: 2.05 by RR4> Incidence rate of CKD: 7.8events/100 P-Y5> Rate of ESRD: 4.9events/100 P-Y

SG Coca et al: AJKD 53: 961-973, 2009 (Yale University)

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%

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/dlS-bilirubin > 1.5 mg/dlCVP ↑: 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 syndrome Hepatorenal 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 oliguriaHyponatremia, dilutional: oftenHyperkalemia, moderate: commonSevere metabolic acidosis→ infectionHemodynamic instability →infectionMajor cause of death: severe bacterial

infection

Hepato-renal syndrome Hepato-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 1500ccProteinuria < 500mg/D; negative sonogram

Hepato-renal syndrome Hepato-renal syndrome (3)(3)

Urine volume < 500ml/DUrine Na < 10meq/LUrine osmolality > plasma osmolalitySerum Na < 130meq/LUrine RBC < 50/HPF

Hepatorenal syndrome Hepatorenal 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 stroke Mortality 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 AKIC.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 RFS-cr 1.5 ～ 3.5

Dye induced nephropathyDye induced nephropathyUniversity 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 nephropathyUniversity 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 syndrome 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 ?

Acute phosphate nephropathyAcute phosphate nephropathyMarkowitz 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 failure Acute renal & hepatic failure

Infectious: Leptospirosis; Hantaan vitus, Reyes syndrome

Toxic: Acetaminophen, methoxyflurane, CCl4, tetracycline in pregnancy

Collagen vascular disease: SLE, PANNeoplastic: RCC, metastatic diseaseGenetic: PCKD, sickle cell diseaseAmyloidosis

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 failuremechanismsmechanisms

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↓