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

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 EtiologyKDIGO-AKI 2012 Guideline

Nutritional support Diuretic role

Renal Replacement Therapy OutcomesSpecific 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

Cr kinetics based definition of AKI Cr 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 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

---

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 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

KDIGO:Grading of evidenceLevel 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 groupEvidence obtained from multiple time series with or without the intervention and uncontrolled trials

PREVENTION AND TREATMENT OF AKI

3.1.1In 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)

3.1.2We recommend the use of vasopressors in

conjunction with fluids in patients with vasomotor shock with AKI or at risk for AKI. (2C)

3.1.3We 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

3.3.1In critically ill patients, we suggest

insulin therapy targeting plasma glucose of 110–149 mg/d (6.1–8.3 mmol/l). (2C)

3.3.2We suggest achieving a total energy intake

of 20–30 kcal/kg/D in patients with any stage AKI. (2C)

3.3.3We suggest avoiding restriction of

protein intake with the aim of preventing or delaying initiation of RRT. (2D)

3.3.4We 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)

3.3.5We 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

3.6.1We recommend not using recombinant

human(rh)IGF-1 to prevent or treat AKI. (1B)

Guideline 3.7: Adenosine receptor antagonists

3.7.1We 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 24 h. (IA)

3.8.4: We suggest monitoring aminoglycoside drug levels when treatment with single-daily dosing is used for more than 48 h. (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 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

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 IHDKt/V targeting 1.2 ～ 1.4 per session with

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

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

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)

Causes of AKI: exposures & Causes of AKI: exposures & susceptibilities forsusceptibilities for

non-specific AKInon-specific AKI

Exposures Susceptibilities

SepsisCritical illnessCirculatory shock BurnsTraumaCardiac surgeryMajor non-cardiac surgeryNephrotoxic drugsRadio-contrast agentsPoisonous plants and animals

Dehydration or volume depletionAdvanced ageFemale Black race CKDChronic diseases(heart, lung, liver)DMCancerAnemia

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 HTNLow GFR: S-Cr > 1.5mg/dl / GFR <

40ml/minR/O shock, infection, toxin, &fluid loss No sustained improvement in renal

function: after diuretic withdrawal/IV NS 1500cc

Proteinuria < 500mg/D; negative sonogramIV albumin: 1.5G/Kg if SBP; 1G/Kg at D3

↓Mortality and ↓renal impairment

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

Risk factors for contrast nephropathy

Iodinated contrast risk factors

DoseIntra-arterial administrationOsmolalityChargeRepeated administration<72 h

Procedure risk factors Interventional versus diagnosticBlood lossHypotension

Patient factors HypovolemiaPre-existing chronic kidney diseaseComorbidity (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

HypotensionIntra-aortic balloon pumpChronic heart failureAge >75 yearsAnemiaDiabetesIodinated contrast volumeSerum creatinine >1.5 mg/dl or eGFR<60 ml/min

Score56-1011-16>16

5554331/100ml42 if eGFR 40–60 ml/min4 if eGFR 20–40 ml/min6 if eGFR<20 ml/min

7.5% risk CN-AKI 0.04% risk dialysis14% risk CN-AKI 0.12% risk dialysis26.1% risk CN-AKI 1.09% risk dialysis57.3% risk CN-AKI 21.6% risk dialysis

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↓

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

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)