classification of the etiologies of acute kidney injury ...€¦ · aaa pvd hypertension...
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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
Acute Interstitial Nephritis:Treatment
Clarkson MR, et al. Nephrol Dial Transplant 2004; 19:2778-2783
Acute Interstitial Nephritis:Treatment
Gonzalez E, et al. Kidney Int 2008; 73:940-946
Acute Interstitial Nephritis:Treatment
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
Strategies for Prevention ofContrast-Induced Nephropathy
Selection of contrast agent HOCM vs. LOCM
LOCM vs. IOCM
Volume administration
Pharmacologic therapy
Hemodialysis and hemofiltration
Avoidance of concomitant nephrotoxins
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
Heinrich MC, et al. Radiology 2009; 250:68-86
Meta-Analysis:Iodixanol vs. Non-Iohexol LOCM
Heinrich MC, et al. Radiology 2009; 250:68-86
Strategies for Prevention ofContrast-Induced Nephropathy
Selection of contrast agent
Volume administration Oral vs. intravenous
Isotonic vs. hypotonic fluids
Saline vs. bicarbonate
Pharmacologic therapy
Hemodialysis and hemofiltration
Avoidance of concomitant nephrotoxins
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
Strategies for Prevention ofContrast-Induced Nephropathy
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
Strategies for Prevention ofContrast-Induced Nephropathy
Selection of contrast agent
Volume administration
Pharmacologic therapy
Hemodialysis and hemofiltration
Avoidance of concomitant nephrotoxins
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
Thakar CV, et al. J Am Soc Nephrol 2005; 16:162-168
≥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
Thakar CV, et al. J Am Soc Nephrol 2005; 16:162-168
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
Friedrich JO, et al. Ann Intern Med 2005; 142:510-524
Low-Dose Dopamine in AKI:Urine Output
Friedrich JO, et al. Ann Intern Med 2005; 142:510-524
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