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A t Kid D f ti i A t Kid D f ti i Acute Kidney Dysfunction in Acute Kidney Dysfunction in the ICU the ICU Slide Sub-Title
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AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

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Page 1: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

A t Kid D f ti iA t Kid D f ti iAcute Kidney Dysfunction in Acute Kidney Dysfunction in the ICUthe ICU

Slide Sub-Title

Page 2: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Learning ObjectivesLearning Objectives

Upon completion of this module you should:Upon completion of this module you should: • Be able to define acute kidney dysfunction and sub-classify it into its

main forms.• Understand the clinical consequences of acute kidney dysfunctionUnderstand the clinical consequences of acute kidney dysfunction.• Be able to list common risk factors for acute kidney dysfunction. • Be able to identify which agents are likely to be useful and which agents

are likely to ineffective or harmful in the prevention and treatment of y pacute kidney dysfunction.

Page 3: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

OutlineOutline

Epidemiology and DefinitionsEpidemiology and Definitions

Etiology/Diagnosis

OOutcome

Prevention

Treatment

Page 4: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Acute Kidney DysfunctionAcute Kidney Dysfunction

Acute kidney dysfunction (AKD) is characterized by abrupt and sustained decline in glomerular filtration rate which gleads to accumulation of urea and other toxins in the blood.• Glomerular filtration rate = rate of transfer of protein free plasma filtrate

(ultrafiltration) across the walls of the glomerular capillaries. ( ) g p• In its most severe form AKD is referred to as acute renal failure.

Until recently, no standard criteria existed for diagnosis and l ifi ti f AKD A t i t ti lclassification of AKD. A recent international,

interdisciplinary consensus panel has classified AKD according to a change from baseline serum creatinine or g gurine output (RIFLE criteria).• RIFLE = Risk, Injury, Failure, Loss, ESKD• ESKD = End-stage kidney diseaseESKD End stage kidney disease

Page 5: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

RIFLE Criteria for Acute Kidney DysfunctionRIFLE Criteria for Acute Kidney Dysfunction

Risk Increased creatinine x 1.5 or GFR decrease >25%

GFR Criteria* Urine Output Criteria

UO <.5ml/kg/hx 6 hrs

HighSensitivity

Injury

%

UO <.5ml/kg/hx 12 hrs

Increased creatinine x 2or GFR decrease >50%

Sensitivity

FailureUO <.3ml/kg/h

x 24 hrs or Increase creatinine x 3

or GFR dec >75% HighFailureanuria x 12 hrsor creatinine ≥4mg/dl

(Acute rise of ≥0.5 mg/dl)

Specificity

Loss

ESRD End Stage Renal Disease

Persistent AKD** = complete loss of renal function > 4 weeks

ESRD g

www.ADQI.netBellomo R, et al. Crit Care. 2004;8:R204–R212.

Page 6: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

RIFLERIFLEAKD is classified according to the worst grade for each domain

(creatinine or urine output). If baseline serum creatinine is abnormal, a smaller relative increase is required to reach “failure.”

Baseline 0.5 (44) 1.0 (88) 1.5 (133) 2.0 (177) 2.5 (221) 3.0 (265)

Risk 0.75 (66) 1.5 (133) 2.3 (200) 3.0 (265) 3.8 (332) ---

Injury 1.0 (88) 2.0 (177) 3.0 (265) --- --- ---

Failure 1 5 (133) 3 0 (265) 4 0 (350) 4 0 (350) 4 0 (350) 4 0 (350)Failure 1.5 (133) 3.0 (265) 4.0 (350) 4.0 (350) 4.0 (350) 4.0 (350)

Creatinine is expressed in mg/dL and (mcmol/L).Creatinine is expressed in mg/dL and (mcmol/L).

Bellomo R, et al. Crit Care. 2004;8:R204–R212.

Page 7: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Epidemiology of AKDEpidemiology of AKD

The prevalence of AKD among patients in the intensive p g pcare unit is not known. • As many as 70% of critically ill patients experience some degree of

AKD.

Approximately 5% of patients in the ICU receive renal replacement therapy (e.g., hemofiltration, hemodialysis).• Hospital mortality in this group is 40 - 80%.

Page 8: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Risk Factors for AKDRisk Factors for AKD

HypovolemiaHypotensionHypotension Sepsis• Frequently as part of multiple organ failureq y p p g

Pre-existing renal, hepatic, or cardiac dysfunctionDiabetes mellitus Exposure to nephrotoxins • Aminoglycosides, amphotericin, immunosuppressive agents, nonsteroidal

anti-inflammatory drugs, angiotensin converting enzyme inhibitors,anti inflammatory drugs, angiotensin converting enzyme inhibitors, intravenous contrast media

Two or more risk factors are usually present.

Page 9: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Types of Acute Types of Acute Kidney DysfunctionKidney Dysfunction

Pre-renal (40 - 80%)Pre renal (40 80%)• renal artery disease• systemic hypotension• Dehydrationy

Intra-renal (10 - 50%)• acute tubular necrosis• interstitial nephritis

Significant overlap

• interstitial nephritis

Post-renal (< 10%)• obstruction

Page 10: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Types of Kidney DysfunctionTypes of Kidney DysfunctionBiochemical indices useful to distinguish a pre-renal from a renal ARF episode

pre-renal renal( O / )osm u (mOsm/kg) > 500 < 400

Na u (mmol/L or meq/L) < 20 > 40

BUN/s creatinine > 20 < 10

u/s creatinine > 40 < 20

u/s osmolality > 1.5 > 1

FeNa (%)* < 1 > 2

________________________________________________________________* ( (u Na / s Na) / (u creat / s creat) ) X 100u for urinary, s for serum, Fe = fractional excretion

Page 11: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Etiology of (intraEtiology of (intra--renal) AKDrenal) AKDand Typical* Urinalysis Findingsand Typical* Urinalysis Findingsand Typical Urinalysis Findingsand Typical Urinalysis Findings

Acute Tubular Necrosis (ATN) [~ 90% of AKD cases]• urine sediment benign mild proteinuria/hematuriaurine sediment benign, mild proteinuria/hematuria• muddy-brown casts

Allergic Interstitial Nephritisi i hil• urine eosinophils

• variable urine sediment, proteinuria and hematuria

Rhabdomyolysisy y• brown urine, dip stick (+) blood but RBC (-) by microscopy• myoglobin (+)

GlomerulonephritisGlomerulonephritis• marked proteinuria• RBC casts (highly specific)

* urinalysis is often non-diagnostic

Page 12: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Cellular Injury and Repair in acute tubular Cellular Injury and Repair in acute tubular necrosis (ATN)necrosis (ATN)necrosis (ATN)necrosis (ATN)

ProliferationAnd

NormalTubular

Injury

PropagationInflammation

Redifferentiation CellsRecovery

(rapid)

Injured Cells

Recovery(slow)

De-Differentiated

Cells ApoptoticCells

Necrotic *Cells

(slow)

* very few necrotic cells are observed from patients with ATN

Cells

ExfoliationInto the Urine

Page 13: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Presence of AKD is Strongly Associated Presence of AKD is Strongly Associated with Hospital Mortalitywith Hospital Mortalitywith Hospital Mortalitywith Hospital Mortality

After adj sting for differences in comorbiditAfter adjusting for differences in comorbidity, AKD was associated with a 5.5 times greater

chance of death compared to matched controlschance of death compared to matched controls without AKD.

Levy et al JAMA 1996;275:1489 94Levy et al. JAMA. 1996;275:1489-94.

Page 14: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Need for Renal Replacement Therapy (RRT) is Need for Renal Replacement Therapy (RRT) is Strongly Associated with Hospital MortalityStrongly Associated with Hospital MortalityStrongly Associated with Hospital MortalityStrongly Associated with Hospital Mortality

Metnitz et al. Intens Care Med. 2002

Page 15: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Metnitz et al. Intens Care Med. 2002

Page 16: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Prevention of AKDPrevention of AKDGoals of therapy are to prevent AKD or need for RRTGoals of therapy are to prevent AKD or need for RRT

Effective Ineffective/harmfulHydrationPrevent hypotension

DiureticsDopamine

Avoid nephrotoxins

UnknownOther renal vasoactive drugs• DA-1 agonists

N-acetylcysteineSodium Bicarbonate

g• PDE inhibitors• Ca++ blockers• Adenosine antagonists

Prophylactic Hemofiltration

g• Natriuretic peptides

Kellum JA, Leblanc M, Venkatraman, R. Clinical Evidence. 2004;11:1094-118.

Page 17: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

PreventionPrevention

Maintain hydration (Isotonic IVF)y ( )Reducing risk from nephrotoxins • Single vs. multiple daily doses of aminoglycosides• Lipid complex vs standard amphotericin• Lipid complex vs. standard amphotericin• Iso-osmomotic vs. standard or “low” osmolality radiocontrast media

Maintain “perfusion pressure” (? Optimal)

Kellum JA, Leblanc M, Venkatraman, R. Clinical Evidence. 2004;11:1094-118.

Page 18: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Should We Use Loop Diuretics to Should We Use Loop Diuretics to Prevent ATN?Prevent ATN?Prevent ATN?Prevent ATN?

Radiocontrast ATNFor prevention (no)

Strength of EvidenceLevel I

Ischemic ATNVascular surgery (no)Oth tti (?)

Level I *No data in humans

Other settings (?)

* diuretics were begun after surgery

Kellum JA. Crit Care. 1997;1:53-59

Page 19: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Dopamine is not EffectiveDopamine is not Effective0.1 1 10

Death All Studies

Excludes Radio-contrast

Heart Disease Only

ARF All StudiesAll Studies

Excludes Radio-contrast

Heart Disease Only

Excludes Outliers

HemodialysisAll Studies

Excludes Radio-contrast

Heart Disease Only

Excludes Outliers

Harm Benefit

Kellum & Decker, Crit Care

Med. 2001;29:1526-1531.

Page 20: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Dopamine is not EffectiveDopamine is not Effective

328 patients in 23 ICUsDopamine 2 μg/kg/min vs. placeboPeak serum creatinine: 245 ± 144 vs. 249 ± 147

l/Lμmol/L# with ARF: 56 vs. 56 # di RRT 35 40# needing RRT: 35 vs. 40ICU LOS: 13 vs. 14 days# f d th 69 66# of deaths: 69 vs. 66

Bellomo et al. Lancet. 2000;356:2139-43.

Page 21: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Dopamine Can Increase Urine Output by Dopamine Can Increase Urine Output by Various MechanismsVarious MechanismsVarious MechanismsVarious Mechanisms

Di t l dil t ti (DA 1 t )Direct renal vasodilatation (DA-1 receptors) Increased cardiac output (β-receptors)I d l f i ( t )Increased renal perfusion pressure (α-receptors)Inhibition of Na-K ATPase at the tubular epithelial cell level resulting in natriuresislevel resulting in natriuresis

Seri I et al. Am J Physiol. 1988;255:F666-73.

Page 22: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Risks of “LowRisks of “Low--dose” Dopaminedose” Dopamine

Bowel mucosal ischemiaBowel mucosal ischemia

Digital necrosis

Pro arrhythmicPro-arrhythmic

Hypo-pituitarism

Immune suppression

Page 23: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Other Vasoactive AgentsOther Vasoactive Agents

DA-1 Agonists Adenosine Antagonistsg• Dopexamine

• Fenoldapam

g• Theophylline• Pentoxifylline• Rolipram

Natriuretic Peptides• Atrial natriuretic peptide

Rolipram

Calcium Antagonists• Nifedipinep p

• Urodilatin• B-type natriuretic peptide

• Diltiazem

Page 24: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

DADA--1 Agonists: Fenoldapam1 Agonists: Fenoldapam

Pure DA-1 effect (no α or β)Pure DA 1 effect (no α or β)

Potent anti-hypertensive

Fi bli h d li i l t i l ( 28 31 45 80 d 315)Five published clinical trials (n = 28, 31, 45, 80 and 315)• Largest: Stone et al. JAMA. 2003;290:2284-91.

- For prevention of contrast nephropathy- No differences between either group in any outcome

Page 25: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Adenosine Antagonists: TheophyllineAdenosine Antagonists: Theophylline

Adenosine decreases renal blood flow (tubular l l f db k)glomerular feedback)

Contrast Nephropathy

C ( )Four RCTs to date (n = 39, 58, 80, 100)• ¾ studies: hydration status is unclear• One study (n = 80) hydration was well defined and no difference

b t t t t d t lbetween treatment and control

CABG patients (n = 56)• No difference

Page 26: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Atrial Natriuretic PeptideAtrial Natriuretic Peptide

Contrast Nephropathy (n = 247, 3-doses)• No effect

ATN (n = 504)• No overall effectNo overall effect• Harm to non-oligurics; benefit in oliguria

Oliguric ARF (n = 220) N ff h i• No effect; hypotension

Urodilatin (ANP analog - no hypotension)• No benefit

Page 27: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

BB--type Natriuretic Peptide (BNP)type Natriuretic Peptide (BNP)

An expensive diuretic?An expensive diuretic? The next “renal dose dopamine”?No data!!No data!!Should be avoided in AKD given results with other natriuretic peptides.

Page 28: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

NN--acetylcysteine (NAC)acetylcysteine (NAC)

83 patients with chronic renal insufficiency (mean crt 2.4) p y ( )CT scans, low-osmolal contrast agent N-acetylcysteine (600 mg p.o. BID) with saline hydration y y ( g p ) yor placebo and saline hydration. Control patients: 21% (9/42) had an increase in crt > 0.5 at 48 h vs 2% of NAC pts (P= 0 01)at 48 h vs. 2% of NAC pts (P= 0.01). The mean crts: NAC: decreased from 2.5 +/- 1.3 to 2.1+/-1.3 (P < 0.001), placebo: increased( ) p

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

Page 29: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

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

Page 30: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

NAC reduces the risk of AKD (increased creatinine) by 50%.

Birck et al. Lancet. 2003;362:598-603.

Page 31: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Does NAC prevent AKD or just decrease Does NAC prevent AKD or just decrease Serum creatinine?Serum creatinine?Serum creatinine?Serum creatinine?

Hoffman et al. J Am Soc Nephrol. 2004;15:407-410.• Healthy volunteers given NAC showed a fall in Scrt without any change

in cystatin C• NAC increases creatinine kinase activity• Increases tubular secretion of creatinine?

Page 32: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

N=154

Does isotonic sodium bicarbonate work better than isotonic sodium chloride solution for prevention of AKD after radiocontrast?

Merten et al. JAMA. 2004;291:(19).

Page 33: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Hemofiltration for RCN?Hemofiltration for RCN?

Marenzi et al. N Engl J Med. 2003;349(2)1333-40.g ; ( )• n = 114, hydration alone vs. hydration plus hemofiltration • > 25% rise in Scrt: 5% vs. 50% P < 0.001• Need for acute RRT post-procedure: 3% vs. 25% P < 0.001Need for acute RRT post procedure: 3% vs. 25% P 0.001• In-hospital mortality: 2% vs. 14% P = 0.02

Results not consistent with hemodialysis studies • Awaiting conformation

Page 34: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

RadioRadio--contrastcontrast

So-called “low osmolality” radio-contrastSo called low osmolality radio contrast• Iohexol: 700 - 800 mOSM• Iodixanol: 200 - 300 mOSM (iso-osmolar)

Incidence of AKD was 3% (iodixanol) compared with 26% (iohexol) (p = 0.002).

Aspelin et al. N Engl J Med. 2003;348:491-9

Page 35: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Treatment of AKDTreatment of AKDGoals of therapy are to prevent death reduce complicationsGoals of therapy are to prevent death, reduce complications,

hasten/permit renal recovery

Effecti e Ineffecti e/harmf lEffectiveHemodialysisBiocompatible

Ineffective/harmfulDiuretics *DopamineBiocompatible

membranesMore dialysis

Dopamine

UnknownCRRT vs. IHDEarlier dialysis

* Diuretics are never a treatment for oliguria but are sometimes required for management of volume overload.

Kellum JA, Leblanc M, Venkatraman, R. Clinical Evidence. 2004; 11:1094-118.

Page 36: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Cumulative Survival vs. Ultrafiltration RateCumulative Survival vs. Ultrafiltration Rate

1001009090 p < 0.001p < 0.001

808070706060

p < 0.001p < 0.001 p n.s.p n.s.60605050

40403030303020201010

41 % 57 % 58 %

00Group 1(n=146)Group 1(n=146)((UfUf = 20 ml/h/Kg)= 20 ml/h/Kg)

Group 2 (n=139)Group 2 (n=139)((Uf Uf = 35 ml/h/Kg)= 35 ml/h/Kg)

Group 3 (n=140)Group 3 (n=140)((UfUf = 45 ml/h/Kg)= 45 ml/h/Kg)

Ronco et al. Lancet. 2000; 355:26-30.

Page 37: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Cumulative Proportion SurvivalCumulative Proportion Survival

1.01.0

.9.9

.8.8

.7.7Group 3Group 3 (p = 0.0013)(p = 0.0013)

.6.6

.5.5

Group 3Group 3

Group 2Group 2 (p = 0.0007)(p = 0.0007)

(p 0.0013)(p 0.0013)

.4.4

.3.3

Group 1Group 1

.2.2

.1.1

.0.0Survival Time (Days)Survival Time (Days) 5050404030302020101000

.0.0

Ronco et al. Lancet. 2000; 355:26-30.

Page 38: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Survival vs. Dialysis Dose In IntermittentSurvival vs. Dialysis Dose In IntermittentH di l iH di l i

100100

HemodialysisHemodialysis

909080807070606050504040 72 %303020201010

54 %

003/wk HD3/wk HD

wKT/V = 3.6wKT/V = 3.67/wk HD7/wk HD

wKT/V = 7.4wKT/V = 7.4

Adapted from Shiffl et al. N Engl J Med. 2002;346:305-10.

Page 39: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Membrane BiocompatibilityMembrane Biocompatibility

199452Schiffl YearN1st Author

1996166Neveu199651Assouad *199557Kurtal

1999160Jorres1998153Himmelfarb 199866Albright *1996166Neveu

1.37

1.46857Combined

2000159Gastaldello1999160Jorres

1* - Abstracts 0.5 2.0

698Excluding Gastaldello

Odds Ratios for Survival

Subramanian et al. Kidney Int. 2002;62:1819-23.

Odds Ratios for Survival

Page 40: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Continuous vs. Intermittent RRTContinuous vs. Intermittent RRT

Unadjusted

0.2 0.6 1 1.4Relative Risk of Death

Insufficient evidence severity thresholdquality threshold

all studies

su c e t e de cefrom published studies to determine which therapy is best Adjusted

quality rawquality wgt

se erit

which therapy is best.

However, CRRT appears to be severity

both q & sTreatment of x-overs*

as CRRT

appears to be superior under most sets of assumptions.

as CRRTexcluded

Favors CRRT

FavorsIRRT

Kellum et al. Intens Care Med. 2002;28:29-37.

Page 41: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

CRRT v IHDCRRT v IHD

• Most recent study (NEJM May 2008)Most recent study (NEJM May 2008)– Multicenter, RCT of CRRT v IHD v SLED

Also compared “low dose” v “moderate dose”– Also compared low dose v moderate dose CRRT (20 cc/kg v 35 cc/kg)

– No difference in renal recovery or mortality– No difference in renal recovery or mortality– BUT:

• Actual dialysis dose delivered was variable• Actual dialysis dose delivered was variable• 35cc/kg may not be enough. > 40cc/kg?

Page 42: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Treatment: DiureticsTreatment: Diuretics

Diuretics: Effects on outcome (small RCTs)( )• 66 patients randomized to receive furosemide (1.5 - 6.0 mg/kg)• No significant differences in recovery or need for HD.

Kl i k ht t l N h 1976 17 51 58Kleinknecht et al. Nephron. 1976;17:51-58.

• 58 patients randomized to single dose (1g) vs. continued dosing of furosemide (3g/day).O 2/30 2 /28• Oliguria was reversed in 2/30 vs. 24/28.

• No differences in mortality, renal recovery, or need for RRT.• Permanent deafness in one patient.

Brown et al. Clin Nephrol. 1981;15:90-6.

Page 43: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Treatment: DiureticsTreatment: Diuretics

Diuretics: Effects on outcome (large observational studies)• 4-center, retrospective analysis of patients referred for nephrology

consults (1989 - 1995; n = 552)• With adjustments for co-variates and propensity score, diuretic use

was associated with:Si ifi l i d i k f d h f l f i– Significantly increased risk of death or non-recovery of renal function (odds ratio 1.77; 95% CI 1.14 - 2.76)

Mehta et al. JAMA. 2002;288:2547-53.

• 52-center, prospective inception cohort of ICU patients (n = 1743)• No differences in mortality, or renal recovery, even after adjustment

for the same co-variates and propensity scoreOdd ti 1 22 ( 0 15)– Odds ratio 1.22 (p = 0.15)

• However, no benefit associated with diuretics either!Uchino et al. Crit Care Med. 2004;32:1669 –77.

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Acute Kidney Dysfunction in the ICUAcute Kidney Dysfunction in the ICU

ConclusionsAKD is a common ICU syndrome.• As many as 70% of ICU patients develop AKD.• Approximately 5% of ICU patients receive RRTApproximately 5% of ICU patients receive RRT.

AKD in the critically ill carries a very high mortality, and current treatment is disappointing.pp g

Inflammation likely plays a significant role in the development of AKD.

Page 45: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Conclusions/RecommendationsConclusions/Recommendations

For Prevention of AKD in the ICU:• Avoid nephrotoxins, hypotension, and dehydration.

- Grades B - D for various options• Don’t use diuretics, dopamine, or other vasoactive drugs.

- Grade A +• N - acetylcysteine + fluids for high-risk patients undergoing radio-

contrast studies.G d A- Grade A -

• Consider bicarbonate-based fluids for prevention of radio-contrast induced AKD.

- Grade CGrade C

Page 46: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

Conclusions/RecommendationsConclusions/Recommendations

For Treatment of AKD in the ICU• Avoid further injury from nephrotoxins, hypotension, and dehydration.

- Grades B - D for various options• Don’t use dopamine or other vasoactive drugs.

- Grade A +• Avoid diuretics.

- Grade D• Use biocompatable membranes.

- Avoid cuprophane (Grade A -)- Avoid cuprophane (Grade A -)- Avoid all cellulosic membranes (Grade C)

• Use 35 ml/kg/min for CRRT and possibly daily dialysis for IRRT.- Grade C

• Use CRRT?• Use CRRT?- Grade D

Page 47: AtKid D f ti iAcute Kidney Dysfunction in the ICU · anti-inflammatory drugs, angiotensin converting enzyme inhibitors,inflammatory drugs, angiotensin converting enzyme inhibitors,

AKD: Special CircumstancesAKD: Special Circumstances

Hepatorenal Syndromep y• profound renal vasoconstriction• low RBF and low GFR• marked Na and water retentionmarked Na and water retention• “pre-renal” urine chemistries• bland pathology and urine sediment• Type I (rapid renal failure) and Type II (diuretic-resistant ascites)Type I (rapid renal failure) and Type II (diuretic resistant ascites)

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Hepatorenal SyndromeHepatorenal Syndrome

Managementg• low Na diet and diuretics• paracentesis• shuntshunt• liver transplant• aquaretic agents (? effectiveness)

• AVP - V2 receptor antagonistsp g• selective kappa-opioid agonists

• vasopressors

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Pathophysiology of HRSPathophysiology of HRS

HRS = arterial hypotension, very low SVRI, very high i NE d ADH d t i ti irenin, NE and ADH, and vasoconstriction in non-

splanchnic arterial vascular territories, including the kidneys, the brain, and the muscle and skin. y

Splanchnic circulation: marked arterial vasodilation = impairment in circulatory function and the homeostatic activation of the endogenous vasoconstrictor systems.

Drug treatment (limited efficacy data)O i i t li i d i• Ornipressin, terlipressin, and vasopressin

• Midodrine (an oral alpha-agonist)

Arroyo V, Jimenez W. J Hepatol. 2000;32:157-70.

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Key ReferencesKey References

1. Lameire N. The pathophysiology of acute renal failure. Crit Care Clin. 2005 21(2) 197 2102005;21(2):197-210.

2. Metnitz PG, Krenn CG, Steltzer H, et al. Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med. 2002;30:2051–2058.2002;30:2051 2058.

3. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–R212.

4. Kellum JA, Leblanc M, Venkataraman R. Acute renal failure. Clin Evid. 2004;(11):1094-118.

5 U hi S D i GS B ll R t l Di ti d t lit i t l5. Uchino S, Doig GS, Bellomo R, et al. Diuretics and mortality in acute renal failure. Crit Care Med. 2004;32:1669-1677.

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Case 1Case 1

A.B. is a 53-year-old male with a past medical history of “poorly controlled” hypertension (taking an ACE inhibitor and a Ca++ channel blocker). He

i h 80 k d t ith t d hi t f f d h dweighs 80 kg and presents with a two-day history of fever and cough, and his chest radiograph shows an RLL infiltrate. His BP on admission is 88/54, and he is given IV fluids (saline) and antibiotics (ampicillin sulbactam).

His admission labs show a serum creatinine of 1.5 mg/dL (133 mcmol/L) and his BUN is 42. Six months ago, his serum creatinine was 1.2. Over the next six hours his urine output is 20 - 30 ml/hr. He is given 2L of 0.9% saline and 500 ml of 5% hetastarch. His BP improves to 110/60 and his pulseand 500 ml of 5% hetastarch. His BP improves to 110/60 and his pulse decreases from 128 to 109. He is admitted to the ward and you are called by his nurse for continued low urine output.

Case 1 page 1

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Case 1 Case 1 (cont.)

The patient’s UO has been < 0.5ml/kg/hr for more than 6 hours. This may indicate AKD (“risk” category for urine output by RIFLE criteria), but it might just as easily represent inadequate circulating blood volume or (much less likely) an obstructive uropathy.

You place a Foley catheter and there is only 20 ml of urine. While this does not rule out obstructive uropathy, it makes it very unlikely. Additional testing (e.g., renal ultrasound) might be indicated if there is still a diagnostic question but pre-renal or intra-renal disease is far more likely.

You send the urine for electrolytes and this reveals a uNa of 10 mmol/L, uCr yof 50 mg/dL, and you calculate a fractional excretion (FE) of Na of 0.5%. These results are consistent with pre-renal disease but urine studies are not themselves diagnostic.

Examination of the urine reveals no WBCs or casts. These findings make interstitial or glomerulular nephritis very unlikely. The absence of muddy brown casts do not exclude the diagnosis of ATN.

Case 1 page 2

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Case 1 Case 1 (cont.)

You also send a repeat BUN and serum creatinine which are 40 and 1.8 mg/dL. The ratio of BUN/creatinine > 20 is consistent with (but not diagnostic g ( gof) pre-renal disease.

You decide to give additional fluid (1L 0.9% saline) over the next hour, but the urine output remains low and the BP decreases to 90/55.p

You now need to establish the etiology of the persistent hypotension. Possibilities include: hypovolemic (even though the patient has received 3.5 L of fluid), septic (distributive), cardiogenic, and obstructive. Options for ) p ( ) g pdetermining the etiology range from noninvasive (e.g., echocardiography) to invasive (e.g., pulmonary arterial catheterization). No technique is completely failsafe but if cardiac output is increased, the diagnosis must be di t ib tidistributive.

Case 1 page 3

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Case 1 Case 1 (cont.)

You determine that the cardiac output is increased and you also measure an arterial lactate (2.7) and mixed venous oxygen saturation (72%). You also d t i th t th t l i 14 H Th fi didetermine that the central venous pressure is 14 mm Hg. These findings make hypovolemia unlikely.

At this point, even though the mean arterial pressure is 62 mm Hg, you are concerned that the patient’s BP is too low and that he may not have adequate perfusion pressure for his organs (including the kidneys). This is a significant concern, especially in a chronic hypertensive. Atherosclerotic disease is likely and a decreased blood pressure may result in insufficient flow. The slightand a decreased blood pressure may result in insufficient flow. The slight elevation in the arterial lactate also suggests this diagnosis.

This scenario is further supported by this combination of urine chemistries (pre-renal) and systemic hemodynamics (hyperdynamic) You decide to(pre renal) and systemic hemodynamics (hyperdynamic). You decide to increase the mean arterial pressure to 70 mm Hg using norepinephrine.

Case 1 page 4

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Case 1Case 1 (cont.)

The patient is given activated protein C and his adrenal axis is evaluated using a short ACTH stimulation test (his response is normal).

Over the course of the next 12 hours, you maintain his mean arterial pressure > 70 mm Hg with 0.02 – 0.04 mcg/kg/min of norepinephrine. His urine output gradually increases, and his central venous pressure falls to 8

H Y d i i t dditi l fl id (l t t d Ri thi ti t idmm Hg. You administer additional fluids (lactated Ringers this time to avoid giving additional saline, which may cause acidosis) and continue supportive care.

Th t d th ti t’ C t i t 2 2 (BUN f ll t 32) R tThe next day, the patient’s Crt increases to 2.2 (BUN falls to 32). Repeat urine electrolytes show an Na of 35 and the FeNa is 1.8. Muddy brown casts appear in the urine. The next day the serum creatinine decreases to 2.0 and his blood pressure improves. You discontinue the norepinephrine and by the p p p p ynext day he is requiring antihypertensive therapy. He makes a complete recovery.

Case 1 page 5

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Case 2Case 2C.D. is a 64-year-old female with a history of hypertension, 3-vessle coronary artery disease, and poor left ventricular function (ejection fraction: 20%). She weighs 80 kg and undergoes coronary arterial revascularization. Th i tf l b t h i fl id d tiThe surgery is uneventful but she requires fluids and vasoactive medications (epinephrine and dobutamine) to come off of cardiopulmonary bypass.

Her initial postoperative care is unremarkable except that she a borderlineHer initial postoperative care is unremarkable except that she a borderline urine output 30 - 40 ml/hr and her blood pressure is very labile.

Her admission labs (drawn 24 hours before surgery) showed a serum creatinine of 1 5 mg/dL (133 mcmol/L) Over the first 24 hours after surgerycreatinine of 1.5 mg/dL (133 mcmol/L). Over the first 24 hours after surgery, she makes 200 mL of urine. Her serum creatinine increases to 2.0 mg/dL (177 mcmol/L). She is maintained on vasoactive medications but is weaned from mechanical ventilation and extubated. Her cardiac function remains poor but cardiac index is 2.2 on epinephrine and dobutamine. She has not received any nephrotoxic agents. Urine chemistries and microscopy are consistent with a diagnosis of ATN.

Case 2 page 1

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Case 2Case 2 (cont.)

The following day her serum creatinine increases to 3.0 mg/dL (266 mcmol/L) and her BUN increases to 65 mg/dL. She has made 300 mL of urine in the last 24 hours, and her total fluid intake has exceeded all output b 11L i th H i ht i 90 k d h h dby 11L since the surgery. Her weight is now 90 kg and she has edema on physical exam.

Furosemide is administered but she does not respond. The next day the creatinine is 4 0 mg/dl and she is started on continuous veno venouscreatinine is 4.0 mg/dl and she is started on continuous veno-venous hemofiltration at an ultrafiltration rate of 35 ml/kg/hr based on her admission weight. Initially 100 mL of fluid are removed per hour and this is increased to 150 mL/h, but her blood pressure becomes unstable, and the removal rate is preturned to 100.

Over the course of the next five days 8L of fluid are removed, and her heart function improves such that all vasoactive medications are discontinued. She is converted to intermittent dialysis and is discharged form the ICU.

A week later renal function gradually recovers, and one month later her serum creatinine has returned to baseline.

Case 2 page 2