classification of the etiologies of acute kidney injury ...€¦ · aaa pvd hypertension...

Acute Kidney Injury:Prevention & Non-Dialytic Therapy

Paul M. Palevsky, M.D.Chief, Renal Section

VA Pittsburgh Healthcare System

Professor of Medicine University of Pittsburgh School of Medicine

AcuteTubularNecrosis

AcuteInterstitialNephritis

AcuteVascular

Syndromes

IntratubularObstruction

PrerenalAKI

IntrinsicAKI

Classification of the Etiologies of Acute Kidney Injury

AcuteKidneyInjury

PostrenalAKI

AcuteGN

AtheroembolicDisease

Prerenal Azotemia

RenalHypoperfusion

DecreasedGFR

Angiotensin II

Adrenergic nerves

Vasopressin

+

+

+

Nitric oxide

Prostaglandins-

-

VolumeDepletion

CongestiveHeart Failure Liver

Failure

Sepsis

RPF

GFR

PGC

Glomerular Hemodynamics in Hyperdynamic Sepsis

AKI in Liver Disease

Pre-renal Azotemia

Hepatorenal Syndrome

Acute Tubular Necrosis

Interstitial Nephritis

Glomerular Syndromes IgA nephropathy

cryoglobulinemia

MPGN

Membranous nephropathy

Renal Dysfunction in Cirrhosis

Diuretic Responsive Ascites

Normal GFR

Diuretic Refractory Ascites

↓GFR

HepatorenalSyndrome

↓↓↓GFR

Arroyo V, et al: Hepatology 1996; 23:164-176

Diagnostic Criteria for Hepatorenal Syndrome Major criteria

Low GFR (SCr > 1.5 mg/dL or CrCl < 40 mL/min) Absence of shock, ongoing bacterial infection, treatment with

nephrotoxins, or fluid losses No sustained improvement in renal function following diuretic

withdrawal and expansion of plasma volume with 1.5 L of isotonic saline

Protinuria < 500 mg/dL and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease

Additional Criteria Urine volume <500 mL/d Urine sodium <10 mmol/L Urine osmolality > plasma osmolality Urine red blood cells < 50 per high power field Serum sodium concentration < 130 mmol/L

Salerno F, et al. Gut 2007; 56: 1310-1318

Revised Diagnostic Criteria for Hepatorenal Syndrome

Cirrhosis with ascites Serum creatinine >1.5 mg/dl No improvement of serum creatinine after at least 2 days

with diuretic withdrawal and volume expansion with albumin The recommended dose of albumin is 1 g/kg of body

weight per day up to a maximum of 100 g/day Absence of shock No current or recent treatment with nephrotoxic drugs Absence of parenchymal kidney disease as indicated by

proteinuria >500 mg/day, hematuria (>50 RBC/hpf) and/or abnormal renal ultrasonography

Pathogenic Mechanisms in Hepatorenal Syndrome

Peripheral and splanchnic vasodilatation without adequate increase in cardiac output

Activation of RAAS, SNS, & Vasopressin

Renal vasoconstrictionSalt and H2O retention

Ascites

HRS

Aggressive diuresisLarge volume paracentesis

SBPBacterial infection

Hemorrhage

Forms of Hepatorenal Syndrome

Type 1 Doubling of serum creatinine to a level of >2.5

mg/dL or a reduction in creatinine clearance by 50% or more to a value of < 20 mL/min over a duration of < 2 weeks

Type 2 Moderate and stable reduction in renal function

Outcomes in Hepatorenal Syndrome

Gines P, et al. Lancet 2003; 362: 1819-827

0 2 4 6 8 10 12

0

0.2

0.4

0.6

0.8

1.0

Sur

viva

l Pro

babi

lity

Months

Type 1 HRS

Type 2 HRSP=0.001

Treatment of Hepatorenal Syndrome

Liver transplantation

Vasoconstrictors Terlipressin

Norepinephrine

Midodrine / Octreotide

Transjugular intrahepatic portosystemicshunting (TIPS)

Renal replacement therapy as bridge therapy

Terlipressin and Albumin in HRS: Reversal of HRS

Martin-Llahi M, et al. Gastro 2008; 134:1352-1359 Sanyal AJ, et al. Gastro 2008; 134:1360-1368

Pro

babi

lity

of R

espo

nse

Days

Terlipressin + Albumin

AlbuminP<0.05

Rev

ersa

l of H

RS

Days

Terlipressin and Albumin in HRS:Survival by Response to Therapy

Martin-Llahi M, et al. Gastro 2008; 134:1352-1359 Sanyal AJ, et al. Gastro 2008; 134:1360-1368

Responders

P<0.003

Pro

babi

lity

of S

urvi

val

Days Months

Nonresponders

Terlipressin and Albumin in HRS:Survival by Treatment Group

Sanyal AJ, et al. Gastro 2008; 134:1360-1368

Terlipressin

Placebo

Months

Pro

babi

lity

of S

urvi

val

Abdominal Compartment Syndrome

Definitions Intra-abdominal hypertension: intra-abdominal pressure ≥12 mm Hg; or

abdominal perfusion pressure <60 mm Hg

Abdominal compartment syndrome intra-abdominal pressure ≥20 mm Hg associated with

one or more organ failures

Abdominal Compartment Syndrome

Systemic effects Cardiac: ↓venous return; ↓C.O.; ↑CVP, PCWP &

SVR

Pulmonary: ↑intrathoracic & airway pressures; ↓PaO2; ↑PaCO2

GI: ↓splanchnic perfusion

CNS: ↑intracranial pressure, ↓perfusion pressure

Kidney: ↓renal perfusion; ↓GFR; ↓urinary output

Abdominal Compartment Syndrome Clinical settings Trauma patients following massive volume

resuscitation Post liver transplant Mechanical limitations to the abdominal wall tight surgical closure burn injuries

Bowel obstruction Pancreatitis

Diagnosis Measurement of intra-abdominal pressure transduction of bladder pressure

Treatment Abdominal decompression

Acute Interstitial Nephritis Acute Interstitial Nephritis

Acute kidney injury due to lymphocytic infiltration of the interstitium

Classic triad of fever

rash

eosinophilia

Acute Interstitial Nephritis

Drug-induced Antibiotics

β-lactams Sulfonamides fluroquinolones Rifampin vancomycin

proton pump inhibitors phenytoin furosemide NSAIDs

Malignancy

Infection-related bacterial viral rickettsial tuberculosis

Systemic diseases SLE sarcoidosis Sjögren’s syndrome tubulointerstitial nephritis

and uveitis

Idiopathic

Acute Interstitial Nephritis:Clinical Presentation

Acute Interstitial Nephritis:Clinical Presentation

Acute Interstitial Nephritis:Eosinophiluria

Muriithi AK, et al. CJASN 2013; 8: 1857-1862

Drug Induced-AIN All Etiologies of AIN

All cases (n=548) Pyuria (n=452) All cases (566) Pyuria ( 467)

>1% >5% >1% >5% >1% >5% >1% >5%

Sensitivity 35.6 23.3 44.8 29.3 30.8 19.8 38.4 24.7

Specificity 68.2 91.2 61.7 89.3 68.2 91.2 61.7 89.3

PPV 14.7 28.8 14.7 28.8 15.6 30.0 15.6 30.0

NPV 87.3 88.6 88.4 89.6 83.7 85.6 84.4 86.5

Positive LR 1.1 2.6 1.2 2.7 0.97 2.3 1.0 2.3

Negative LR 0.9 0.8 0.9 0.8 1.01 0.9 1.0 0.8

Acute Interstitial Nephritis:Treatment

Discontinue offending drug

Treat underlying infection

Treat systemic illness

Glucocorticoid therapy recommended in patients who fail to respond to

more conservative therapy

no RCTs have been reported


Clarkson MR, et al. Nephrol Dial Transplant 2004; 19:2778-2783


Gonzalez E, et al. Kidney Int 2008; 73:940-946


Fin

al s

eru

m c

rea

tinin

e (

mg

/dL)

Gonzalez E, et al. Kidney Int 2008; 73:940-946

Acute Vascular Syndromes

Macrovascular Renal artery thromboembolism

Renal artery dissection

Renal vein thrombosis

Microvascular Atheroembolic disease

Atheroembolic Disease

Atheroembolic Disease

Risk factors Atherosclerosis

CAD

AAA

PVD

Hypertension

Hypercholesterolemia

Diabetes Mellitus

Precipitating factors Arterial catheterization

Arteriography

Vascular surgery

Anticoagulation

Thrombolytic therapy

Atheroembolic Disease:Non-Renal Manifestations General

Fever Myalgias Weight loss

Cutaneous Livedo reticularis Digital ischemia

Neurologic TIA/CVA Altered mental status Peripheral neuropathy Spinal cord infarct

Gastrointestinal Anorexia Nausea and vomiting Nonspecific abdominal pain GI bleeding Ileus Bowel ischemia/infarction Pancreatitis Hepatitis

Musculoskeletal Myositis

Eyes Amaurosis fugax Retinal cholesterol emboli

Atheroembolic Disease:Renal Manifestations

Renal infarction

Acute kidney injury

Subacute kidney injury

Exacerbation of hypertension

Proteinuria (may be nephrotic)

Hematuria

Atheroembolic Disease:Laboratory Features

Serum chemistries ⇑BUN and creatinine

⇑Amylase

⇑CPK

⇑LFTs

Hematology Leukocytosis

Eosinophilia

Anemia

Thrombocytopemia

Serologic ⇑ESR

⇓Serum complement

Urine Eosinophiluria

Proteinuria

Hematuria

Pyuria

Atheroembolic Disease:Treatment

Avoid anticoagulation

Avoid vascular interventions

ACE inhibitors / angiotensin receptor blockers

Statin therapy

Nutrition support

Dialysis for management of volume status and uremia

Role to steroid therapy is uncertain

Intratubular Obstruction

Intratubular Obstruction

Protein Multiple myeloma

Crystals Uric Acid

Oxalate

Medications

The Kidney in Multiple Myeloma

Light chain cast nephropathy (myeloma kidney)

Hypercalcemic nephropathy

Acute uric acid nephropathy

Plasma cell infiltration of the kidney

Hyperviscosity syndrome

AL amyloidosis

Light-chain deposition disease

Proximal tubular dysfunction (acquired Fanconi’s syndrome)

Treatment of Myeloma Cast Nephropathy

Correction of volume depletion / saline diuresis

Correction of hypercalcemia

Correction of hyperuricemia

Reduction in light-chain burden

Chemotherapy

Extracorporeal removal Plasmapheresis

Hemodialysis with high cut-off membrane

Treatment of Myeloma Cast Nephropathy

Hutchison CA, et al. JASN 2011;22:1129-1136

Tumor Lysis Syndrome Tumor Lysis Syndrome

Purine Catabolism

Hypoxanthine

Xanthine

xanthine oxidase

Uric Acid

xanthine oxidase

Allantoin

uricase

allopurinol

_

_

rasburicase+

Drug-Induced Crystal NephropathiesSulfa Crystals Acyclovir Crystals

Indinavir Crystals

Methotrexate Nephropathy

Mallipattu SK, Ross MJ. Kidney Int 2011; 80:226

Acute Tubular Necrosis Acute Tubular Necrosis

Ischemic prolonged prerenal

azotemia

hypotension

hypovolemic shock

cardiopulmonary arrest

cardiopulmonary bypass

Sepsis

Nephrotoxic drug-induced

radiocontrast agents

aminoglycosides

vancomycin

amphotericin B

cisplatin

acetaminophen

pigment nephropathy

hemoglobin

myoglobin

Acute Tubular Necrosis:Urine Sediment Prevention and Treatment of AKI

GF

R

Time

Prevention of ATN

Requirements Identification of high risk patients

Timed insult

Potential settings Radiocontrast administration

Cardiovascular surgery

Rhabdomyolysis

Pathophysiology ofContrast-Induced Nephropathy

Radiocontrast Administration

IntrarenalVasoconstriction

DirectCytotoxicity

Altered BloodRheology

Generation of ROS

Radiocontrast Nephropathy

OsmoticLoad

Medullary Hypoxia

Risk Factors for Contrast-Induced Nephropathy

Patient Related Preexisting renal insufficiency

Diabetes mellitus

Intravascular volume depletion

Reduced cardiac output

Concomitant nephrotoxins

Procedure related Increased dose of radiocontrast

Multiple procedures within 72 hours

Intra-arterial administration

Type of radiocontrast

Strategies for Prevention ofContrast-Induced Nephropathy

Selection of contrast agent

Volume administration

Pharmacologic therapy

Hemodialysis and hemofiltration

Avoidance of concomitant nephrotoxins


Selection of contrast agent HOCM vs. LOCM

LOCM vs. IOCM





Radiocontrast Media

High Osmolality (HOCM) Diatrizoate (Hypaque, Renografin, Urografin) Iothalamate (Conray) Metrizoate (Isopaque)

Low Osmolality (LOCM) Ionic

Ioxaglate (Hexabrix) Non-ionic

Iohexol (Omnipaque) Iopamidol (Isovue) Iopromide (Ultravist) Ioversol (Optiray)

Iso-Osmolar (IOCM) Iodixanol (Visipaque)

Relative Nephrotoxicity of HOCM and LOCM

Subgroup Studies SubjectsOdds-Ratio

(95% CI)NNT

Prior renal insufficiency

with 8 1,418 0.50 (0.4-0.70) 8

without 20 2,865 0.75 (0.5-1.1) 30

Injection route

intravenous 14 1,187 0.64 (0.3-1.3)

intraarterial 12 3,000 0.62 (0.5-0.8)

Contrast medium

ioxaglate 4 173 0.46 (0.15-1.3)

non-ionic 22 4,061 0.63 (0.5-0.8)

Barrett BJ, et al. Radiology 1993; 188:171-178

NEPHRIC Study: Iodixanol vs. Iohexol

0

2

4

6

8

10

12

14

16

18

≥0.5 mg/dL ≥1.0 mg/dL

Iodixanol

Iohexol

Aspelin P, et al. N Engl J Med 2003; 348:491-499

Num

ber

of P

atie

nts

Peak Increase in Serum Creatinine

Meta-Analysis:Iodixanol vs. LOCM

Heinrich MC, et al. Radiology 2009; 250:68-86

Meta-Analysis:Iodixanol vs. Iohexol Subgroup


Meta-Analysis:Iodixanol vs. Non-Iohexol LOCM




Volume administration Oral vs. intravenous

Isotonic vs. hypotonic fluids

Saline vs. bicarbonate




Isotonic Saline Prophylaxis of Contrast Nephropathy

Trivedi HS, et al. Nephron Clin Pract 2003; 93:c29-c34

Incidence of ARF: 3.7% 34.6%

Prevention of CIN:Isotonic vs Half-Isotonic Saline

Mueller C, et al. Arch Int Med 2002; 162:329-336

Prevention of CIN:Sodium Bicarbonate vs. Saline

Merten GJ, et al. JAMA 2004; 291:2328-2334

Pre-procedure fluids 3 mL/kg/hr for 1 hour 3 mL/kg/hr for 1 hour

Post-procedure fluids 1 mL/kg/hr for 6 hours 1 mL/kg/hr for 6 hours

Incidence of AKI 13.6% 1.7%

Prevention of CIN: Meta-Analysis of Sodium Bicarbonate Studies

Jang JS, et al. Circ J 2012; 76: 2255-2265


Selection of contrast agent Volume administration Pharmacologic therapy Diuretics Vasodilators Adenosine antagonists Anti-oxidants Statins Iron chelators

Hemodialysis/hemofiltration Avoidance of concomitant nephrotoxins

Prevention of CIN: Saline, Furosemide and Mannitol

Solomon R, et al. N Engl J Med 1994; 331:1416-1420

11%

28%

40%

0%

10%

20%

30%

40%

50%

Saline Mannitol + Saline Furosemide + Saline

≥0.5

mg/

dL in

crea

se in

SC

r

Prevention of CIN: Forced Euvolemic Diuresis with Furosemide and Mannitol

Majumdar SR et al. Am J Kidney Dis 2009; 54:602-609

Per

cent

(%

)

p=0.05 p=0.002 p=0.03

Prevention of CI-AKI with Matched Forced Saline Diuresis: REMEDIAL II

Briguori C et al. Circulation 2011; 124: 1260-1269

20.5%(30/146)

11%(16/146)

0%

5%

10%

15%

20%

25%

Control RenalGuard

Development of CI-AKI

Time (hours)

Ser

um C

reat

inin

e (m

g/dL

)

ControlRenalGuard

2.2

2.0

1.8

1.6

1.4

1.2

1.0

2.4

Baseline 24 48

Prevention of CI-AKI with Matched Forced Saline Diuresis: REMEDIAL II

Briguori C et al. Circulation 2011; 124: 1260-1269

4.0

0 30 60 90 120 150 180 210 240 270 300 330 360 390

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

Time (min)

Vol

ume

(L)

InfusionUrine

Prevention of CIN: Theophylline

Dai B, et al. Am J Kidney Dis 2012; 60: 360-370

Odds Ratio for Developing Radiocontrast Nephropathy

Prevention of Contrast-Induced Acute Kidney Injury: Theophylline

Dai B, et al. Am J Kidney Dis 2012; 60:360-370

Odds Ratio for Developing Radiocontrast-Induced Acute Kidney InjuryStratified by Baseline Kidney Function

Prevention of CIN: N-Acetylcysteine

Tepel M, et al. N Engl J Med 2000; 343:180-184

Change in serum creatinine At 48 hours

Percent patients with increasein serum creatinine 0.5 mg/dL

NAC Control

-1

-0.5

0

0.5

1

seru

m c

reat

inin

e (m

g/d

L)

Kelly AM, et al. Ann Intern Med 2008; 48:284-294

Meta-Analysis: N-Acetylcysteine for Prevention of CIN

OR 0.46; 95% CI: 0.33-0.63

Study N % CINControl NAC

Durham (2002) 79 22.0% 26.3%Baker (2003) 80 20.5% 4.9%Kefer (2003) 104 5.9% 3.8%Oldemeyer (2003) 96 6.4% 8.2%Efrati (2003) 49 8.0% 0.0%Goldenberg (2004) 80 7.7% 9.8%Miner (2004) 180 22.4% 9.5%Ochoa (2004) 80 25.0% 8.3%Rashid (2004) 94 6.2% 6.5%Balderramo (2004) 61 10.7% 3.0%Marenzi (2006) 237 32.8% 8.5%Khalili (2006) 70 17.1% 5.7%Poletti (2007) 87 16.3% 4.5%Shaikh (2007) 161 13.8% 9.9%Shaikh (2007) 159 7.6% 10.0%Heng (2007) 60 6.2% 3.6%

Summary

Meta-Analysis: High-Dose N-Acetylcysteine for Prevention of CIN

Trivedi H, et al. Am J Med 2009; 122: 874e9-874e15

Acetylcysteine for the Prevention of Contrast-Induced nephropaThy (ACT) Trial

Berwanger O, et al. Circulation 2011; 124: 1250-1259

Endpoint Acetylcysteine Placebo RR (95% CI)

p

Increase in serum creatinine at 48 to 96 hours

>25% 147/1153 (12.7%)

142/1119(12.7%)

1.00 (0.81 - 1.25)

0.97

>0.5 mg/dL 45/1153(3.9%)

42/1119(3.8%)

1.04 (0.69 - 1.57)

0.85

>100% 13/1153(1.1%)

17/1119(1.5%)

0.74 (0.36 - 1.52)

0.41

Death or dialysis at 30 days 26/1171(2.2%)

26/1135(2.3%)

0.97(0.56 - 1.69)

0.92

Although the ACT study is the largest RCT of NAC to date (N=2308), the results need to be interpreted with caution:

Baseline serum creatinine obtained up to 90 days pre-procedure

Only 15.7% of patients with a baseline serum creatinine >1.5 mg/dL

>20% of procedures performed using HOCM

Periprocedural fluid administration not standardized

Acetylcysteine for the Prevention of Contrast-Induced nephropaThy (ACT) Trial

Berwanger O, et al. Circulation 2011; 124: 1250-1259

Statin-treated Statin-naive

Prevention of CIN: Statins – Observational Data

Patti G, et al. Am J Cardiol 2008; 101: 279-285

Per

cent

(%

)

p=0.0001

Cre

atin

ine

Cle

aran

ce (

mL/

min

)

p=0.87 P<0.0001

Prevention of CIN: RCT of Atorvostatin

Toso A, et al. Am J Cardiol 2010; 105:288-292

Per

cent

(%

)

NS

NS

Prevention of CI-AKI with Short-Term Rosuvastatin Administration

0%

4%

8%

12%

16%

20%

Rosuvastatin Control0%

4%

8%

12%

16%

20%

Rosuvastatin Control

58/15003.9%

17/2526.7%

38/25215.1%

OR: 0.5895% CI: 0.38-0.89

P=0.01

OR: 0.4195% CI: 0.22-0.74

P=0.003

Han Y, et al. JACC 2014; 63: 62-70 Leoncini M, et al. JACC 2014; 63: 71-79

34/14982.3%

40 mg then 20 mg/day10 mg/day







Meta-Analysis of RRT for Prevention of CI-AKI

Cruz DN, et al. Am J Med 2012; 125:66-78

Study or SubgroupRRT Standard Treatment

Risk Ratio (95% CI)Total Events Total Events

HF-HDF

Gabutti (2003) 24 9 25 6 1.56 (0.66 – 3.72)

Marenzi (2003) 58 4 56 32 0.12 (0.05 – 0.32)

Marenzi (2006) 62 14 30 14 0.48 (0.27 – 0.88)

Total 144 27 111 52 0.46 (0.12 – 1.70)

Heterogeneity: Tau2 = 1.17; Chi2 = 15.95 (p=0.0003); I2 = 0.87

Test for overall effect: Z = 1.17 (p=0.24)

IHD

Berger (2001) 7 3 8 1 3.43 (0.45 – 25.93)

Hsieh (2005) 20 0 20 1 0.33 (0.01 – 7.72)

Lehnert (1998) 15 8 15 6 1.33 (0.61 – 2.91)

Reinecke (2007) 113 18 229 13 2.81 (1.43 – 5.52)

Sterner (2000) 15 6 17 4 (1.70 (0.59 – 4.90)

Vogt (2001) 55 24 58 20 1.27 (0.80 – 2.01)

Total 225 59 347 45 1.61 (1.13 – 2.28)

Heterogeneity: Tau2 = 0.02; Chi2 = 5.42 (p=0.37); I2 = 0.08

Test for overall effect: Z = 2.26 (p=0.008)

Risk Ratio (95% CI)

0.01 0.1 10 1001

Favors RRT Favors Std Treatment

Hemofiltration for Prevention of Contrast-Induced Nephropathy

Marenzi G, et al. N Engl Med 2003; 349:1333-1340

5

4

3

2

1

0

Ser

um C

reat

inin

e (m

g/dL

)

Baseline Pre-Procedure Day 1 Day 2 Day 3 Discharge

CONTROL

CVVH

5

4

3

2

1

0

Ser

um C

reat

inin

e (m

g/dL

)

Baseline Pre-Procedure Day 1 Day 2 Day 3 Discharge

CONTROL

PRE-CVVH

POST-CVVH

Marenzi G, et al. Am J Med 2006; 119:115-162

Impact of RAAS Blockade on Contrast-Induced Nephropathy

Rosenstock JL, et al. Int Urol Nephrol 2008; 40: 749-755

De

velo

pm

en

t of C

IN (

%)

(n=113) (n=63)(n=107)

*randomized‡non-randomized

‡

p=0.66

The Effect of Small Changes in Serum Creatinine on Apparent Incidence of AKI

IncreaseDecreaseSerum Creatinine

AKI

Interventions Which May Decrease Serum Creatinine

ECF volume expansion

Isotonic bicarbonate?

(volume of distribution smaller than for saline)

Theophylline?

N-acetylcystine?

Rosuvastatin

Renal replacement therapy

Discontinuation of ACE-I/ARB

Strategies for Prevention ofContrast-Induced Nephropathy Effective

Low- or Iso-osmolal contrast agents Intravenous isotonic fluids Avoidance of concomitant nephrotoxins

Ineffective or harmful Furosemide Manitol Dopamine Fenoldopam Prophylactic RRT

Uncertain Intravenous sodium bicarbonate N-acetylcysteine Theophyliine ANP Statins Iron chelators

Recommendations for Prevention of Contrast-Induced Nephropathy

Identify high risk patients Use low osmolar or iso-osmolar contrast in high-risk

population Volume expand with isotonic sodium chloride or

sodium bicarbonate Optimal fluid composition and timing and rate of

fluid administration remain uncertain N-acetylcysteine Although data are inconclusive, NAC is

inexpensive and safe Discontinue NSAIDs

AKI after Cardiac Surgery

Risk Factor Estimate (CI) P Value Points

Female gender 0.48 (0.21–0.75) <0.001 1

Congestive heart failure 0.48 (0.20–0.76) <0.001 1

Left ventricular ejection fraction <35% 0.39 (0.07–0.71) 0.016 1

Preoperative use of IABP 1.08 (0.49–1.67) <0.001 2

COPD 0.70 (0.37–1.04) <0.001 1

Insulin-requiring diabetes 0.40 (0.05–0.76) 0.026 1

Previous cardiac surgery 0.54 (0.28–0.81) <0.001 1

Emergency surgery 1.13 (0.65–1.60) <0.001 2

Surgery type

valve only 0.45 (0.10–0.80) 0.013 1

CABG + Valve 0.86 (0.53–1.19) <0.001 2

other cardiac surgeries 1.02 (0.56–1.49) <0.001 2

Preoperative creatinine 1.2 to <2.1 mg/dl 0.92 (0.64–1.21) <0.001 2

Preoperative creatinine ≥2.1 mg/dl 2.66 (2.28–3.04) <0.001 5

Thakar CV, et al. J Am Soc Nephrol 2005; 16:162-168

Prediction of Severe AKI after Cardiac Surgery

0%

10%

20%

30%

40%

50%

60%

0-2 3-5 6-8 9-13

Incidence of AKI Patients Patients with AKI

Predictive Score


≥3 ≥6 ≥9

Specificity 55% 92% 99%

Sensitivity 88% 51% 12%

PPV 3% 10% 21%

NPV 99.6% 99% 98%

Prediction of Severe AKI after Cardiac Surgery

1-specificity

sens

itvity


AUC ≈ 0.8

Interventions to Decrease the Risk of Post-Cardiac Surgery AKI

Effective Optimization of volume status Avoidance of nephrotoxins Minimization of CPB time Off-pump surgery Discontinuation of NSAIDs Pre-operative discontinuation

of RAAS blockade Avoidance of hyperglycemia

Questionably Effective Fenoldopam rhANP

Ineffective Dopamine Diuretics Theophylline Bicarbonate N-acetylcysteine

CORONARY Study:Off-Pump or On-Pump CABG

Outcome Off-Pump(N=2375)

On-Pump(N=2377)

Hazard Ratio(95% CI)

P Value

Primary outcome 9.8% 10.3% 0.95 (0.79-1.14) 0.59

Death 2.5% 2.5% 1.02 (0.71-1.46)

MI 6.7% 7.2% 0.93 (0.75-1.15)

Stroke 1.0% 1.1% 0.89 (0.51-1.54)

Dialysis 1.2% 1.1% 1.04 (0.61-1.76)

AKI

AKIN definition 28.0% 32.1% 0.87 (0.80-0.96) 0.01

RIFLE-R 17.0% 19.5% 0.87 (0.76-0.98) 0.02

RIFLE-I 6.1% 7.4% 0.83 (0.66-1.03) 0.09

RIFLE-F 2.0% 2.6% 0.77 (0.52-1.13) 0.18

Lamy A, et al. N Engl J Med 2012; 366:1489-1497

Prevention of AKI in Non-Cardiac Surgery

Goal-directed peri-operative hemodynamic management

Avoidance of intra-operative hypotension

Avoidance of NSAIDs

Intraoperative BP and Risk of AKI in Non-Cardiac Surgery

<55 mmHg

55 -59 mmHg

60-64 mmHg65-69 mmHg70-74 mmHg

Walsh M, et al. Anesthesiology 2013; 119: 507-515

Duration of Hypotension and Risk of AKI in Non-Cardiac Surgery

Walsh M, et al. Anesthesiology 2013; 119: 507-515

Prevention of Myoglobinuric AKI

Standard management recommendations Aggressive intravenous fluids

Bicarbonate

Mannitol

Prevention of Myoglobinuric AKIRole of Mannitol and Bicarbonate

0%10%20%30%40%50%60%70%

5-15 15-30 >30

CPK (1000 U/L)

Acute Renal Failure

0%

10%

20%

30%

40%

5-15 15-30 >30

CPK (1000 U/L)

Dialysis

Brown CVR, et al. J Trauma 2004; 56:1191-1196

Pharmacologic Treatment ofEstablished AKI

Dopamine

Fenoldopam

Loop diuretics

Atrial natriuretic peptide

Insulin-like growth factor-I

Thyroxine

Low-Dose Dopamine in AKI: Need for RRT

Friedrich JO, et al. Ann Intern Med 2005; 142:510-524

Low-Dose Dopamine in AKI: Mortality


Low-Dose Dopamine in AKI:Urine Output


Diuretic Therapy in ATN

Mehta RL, et al. JAMA 2002; 288:2547-2553

Diuretic Use and Fluid Balance in AKI: Post-Hoc Analysis of FACTT

AdjustmentPost-AKI Fluid

Balance(per mean L/Day)

Post-AKI Furosemide Dose

(per mean 100 mg/Day)

OR (95% CI)

P-valueOR

(95% CI)P-value

None (univariate)1.73

(1.47–2.03)<0.001

0.38(0.23-0.63)

<0.001

Full model1.61

(1.29-2.00)<0.001

0.54(0.31-0.94)

0.028

+Post-AKI fluid balance0.73

(0.42-1.26)0.255

+Post-AKI furosemide dose1.56

(1.25-1.95)<0.001

Final model1.61

(1.32-1.96)<0.001

0.48(0.28-0.81)

0.007

Grams ME, et al. Clin J Am Soc Nephrol 2011; 6:966-973

Pharmacologic Therapy of AKI

Reasons for Lack of Success Differences between animal models and human

disease

Late application of interventions in human disease

Phases of Post-Ischemic AKI

GF

R

Time

Se

rum

Cre

atin

ine

Anaritide for ATN

43%

27%

48%47%

8%

59%

0%

20%

40%

60%

80%

All Patients Oliguric Non-Oliguric

Anaritide Placebo

Allgren RL, et al. N Engl J Med 1997; 336:828-834

p=0.35

p=0.008

p=0.03

Dia

lysi

s-F

ree

Sur

viva

l

Anaritide Placebo Anaritide Placebo

Serum creatinine at enrollment (mg/dL) 4.4±1.7 5.0±2.6 4.4±1.4 4.5±1.7

Death

AKIN Conceptual Modelfor Acute Kidney Injury

NormalIncreased

riskKidneyfailure

Damage GFR

CreatinineIdeal Biomarker

Candidate Biomarkers in AKI

N-acetyl-β-D-glucosaminidase(NAG)

Neutrophil gelatinase-associated lipocalin (NGAL)

Kidney injury molecule-1 (KIM-1)

Interleukin-18 (IL-18)

Fatty acid binding protein (FABP)

Cystatin C

α-1-microglobulin

β-2-microglobulin

Matrix metaloprotinase-9 (MMP-9)

TIMP-2 * IGFBP7

Na+/H+ exchange isoform 3 (NHE3)

Adenosine deaminase binding protein

Alanine aminopeptidase Leucine aminopeptidase β-galactosidase α-glutathione S-transferase (α-

GST) π-glutathione S-transferase (π-

GST) Alkaline phosphatase Lactate dehydrogenase (LDH) Neutral endopeptidase

Retinol binding protein

Prevention and Treatment of AKI

Volume expansion with isotonic crystalloid

Avoid hypotension

Prevent sepsis

Discontinue nephrotoxins

classification of the etiologies of acute kidney injury ...€¦ · aaa pvd hypertension...

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