M I T C H E L L R O S N E R , M D

C h a i r m a n , D e p a r t m e n t o f M e d i c i n e

U n i v e r s i t y o f V i r g i n i a H e a l t h S y s t e m

Acute Kidney Injury Is there a Best Practice?

Disclosures

Consultant: Johnson and Johnson, Otsuka America, Novartis

Overview

3

• Epidemiology

• Diagnosis: Definitions and role of biomarkers

• Prevention strategies

• Therapeutic issues

AKI: Increased Frequency

4

A. Ishani, ASN 2009 and

USRDS Annual Report, 2009 S.M. Bagshaw,

Div Critical Care U. Edmonton

Medicare

Uchino, S. et al. JAMA 2005;294:813-818.

Epidemiology:

A large multicenter observational

study of 29,260 patients:

-5.7 % incidence of severe ARF

requiring RRT

-Overall hospital mortality of ARF

in setting of sepsis was 60.3%

Most common contributing

factors: sepsis and major

surgery. Importantly, drug-

induced ARF in 19%

Epidemiology: Patients with AKI are becoming more

complex

D-CI 3 Mechanical

Ventilation

P<0.001

P<0.001

High Co-morbidity

16.4 26.6 18.0 32.4

D-CI = 0

P<0.001

% P

ati

ents

wit

h A

RF

Low Co-morbidity

1988

2002

0

10

20

30

40

D-CI: Deyo-Charlson Index (0-5+) S. S. Waikar et al JASN 17:1143-1150, April 2006

0

4

8

12

16

20

0%

10%

20%

30%

40%

50%

≥0.3 mg/dL ≥0.5 mg/dL ≥0.5 mg/dL or ≥1.0 mg/dL*

≥1.0 mg/dL ≥2.0 mg/dL 25% 50% 100% 50% AND creatinine≥2.0

mg/dL

Mo

rta

lity

(O

R)

AK

I (%

)

Defining AKI: Problematic in the Past

Depending upon the definition, AKI is associated with

variable mortality

R. Bellomo Crit Care. 2004; 8(4): R204–R212. R.Mehta Crit Care 11 : R31 , 2007 8

Definition of AKI: What is baseline Cr?

AKIN RIFLE

New definitions of AKI (RIFLE, AKIN) use change in

serum creatinine (SCr) from “baseline” to ascertain

disease

Newer KDIGO criteria combine these

definitions

Sepsis and Mortality: AKIN and RIFLE

Hoste et al CCM 2008

AKI: Long-term Outcomes

10

Cerda et al, CJASN 3: 881-6, 2008

11

562,799 patients with MDRD GFR

≥45 ml/min/1.73m2 before

hospitalization

Dialysis-requiring AKI/ARF defined

as both:

Peak inpatient SCr ≥50% higher

than the last observed pre-

admission outpatient SCr AND

Receipt of dialysis during

hospitalization (ICD-9 procedure

codes 54.98, 39.95; CPT codes

90935, 90937, 90945, 90947 and

90999)

Risk of Progressive CKD (Stage 4 or Higher) after AKI

Non-AKI Controls (No

ESRD cases)

AKI Cases (included 41

cases of ESRD)

Lowell J. Lo et al. CJASN 2010

AKI and Progression of CKD following

Coronary Angiography 12

No AKI

Mild AKI

Moderate / severe AKI

40

50

60

70

eG

FR

(m

L/m

in/1

.73

m

2

), m

ean

(95

%C

I)

Pre- 3 24angiogram months months

0.1 mL/min/1.73m2/yr

1.1 mL/min/1.73m2/yr

3.1 mL/min/1.73m2/yr

No

AKI

AKI Stage 1

AKI Stage 2/3

M.T. James. Kidney Injury and Progression of Chronic Kidney Disease following Coronary Angiography

APPROACH coronary angiography registry: All patients undergoing coronary

angiography in Alberta n=20,640 final cohort study n=9,819)

No AKI

AKI Stage 1

AKI Stage 2/3

Biomarkers and AKI

Need for Biomarkers

High risk Prerenal AKI AKI

Therapeutic Window

GFR

- Sensitive

Biomarkers + Creatinine

Benefit of therapies may be limited by a narrow time period

of efficacy

Sensitive biomarkers to detect early and

sub-lethal injury

Rises 24-48

hours after AKI is

established

Courtesy of Dr. Mark Okusa

By the time Scr rises, the injury

has already occurred and

interventions may be too late

What Can An Ideal

AKI Biomarker Teach Us? 15

Predict and diagnose AKI early (before increase in serum creatinine)

Identify the primary location of injury (proximal tubule, distal tubule, interstitium)

Pinpoint the type (pre-renal, AKI, CKD), duration and severity of kidney injury

Identify the etiology of AKI (ischemic, septic, toxic, combination)

Predict clinical outcomes (dialysis, death, length of stay)

Monitor response to intervention and treatment

Expedite the drug development process (safety)

P. Devarajan: Biomarkers in Acute Kidney Injury :Search for a Serum Creatinine Surrogate, ASN 2009

Modified from Vaidya et al. Annu Rev Pharmacol Toxicol 2008

2. Tubular

damage –

Renal injury

1. Normal

epithelium

3. Cell

death

4. Renal function↓

Novel Renal Biomarkers

Urinary Biomarker Performance

Biomarker performance

Time from insult

Baseline eGFR

Complex sensitivity

Complex specificity

More studies required

Endre et al. Kidney Int 2011:

79: 1119

Preventing AKI

Prevention

Given the impact of AKI, it is important to prevent or hasten the resolution of even mild forms of AKI

Goals:

Preserve renal function

Prevent death

Prevent complications of AKI (volume overload, acid-base/electrolyte abnormalities)

Prevent need for chronic dialysis

Minimize adverse effects

Relies on implementation of:

Nonpharmacological strategies

Pharmacological strategies

Renal replacement strategies

Steps in a preventive strategy

1. Identify high-risk patients

2. Non-pharmacological techniques

3. Pharmacological techniques

4. Cause-specific therapies

Often, other care measures not directly targeted to the kidney may have great impact but are not well studied

For example: time to antibiotic initiation, correct antibiotic choice, packed red blood cell transfusions, etc.

Competing influences on outcomes-

complex background of care

40

45

50

55

60

65

70

75

80

0102030405060708090

100

<1 1-2 2-3 3-12 12-24 >24

Inci

de

nce

AK

I (%

)

Cu

mu

lati

ve E

ffe

ctiv

e

An

tim

icro

bia

l Th

era

py

(%)

Time from Onset of Hypotension (hrs)

Antimicrobial Therapy AKI

Adapted from Bagshaw S, Curr Drug Targets 2009

Common risk factors for AKI

Clinical settings: ICU/multiple organ failure Sepsis/infection Post-operative (esp. cardiac

and vascular) Trauma/Burns HIV Non-renal solid organ

transplantation Bone marrow

transplantation Liver disease

Nearly 2/3rds of patients with AKI suffer more than one insult

Patient-specific factors:

Advanced age (more than 70% of cases occur in those age > 70)

Diabetes mellitus

Impaired renal function (most powerful risk)

Impaired cardiac function

Volume depletion/hypotension

Multiple nephrotoxic medications

Radiocontrast exposure

Risks for AKI- cont’d

Medications/toxins NSAIDS/Cox-2 inhibitors

Aminoglycoside antibiotics

Amphotericin B

ACE-inhibitors/ARBS

Calcineurin inhibitors

Chemotherapeutic agents (cisplatin, ifosfamide)

Toxic ingestions

Occupational toxins (solvents, heavy metals)

Herbal remedies

Once daily dosing

Liposomal/lipid formulations

Specific antidotes (fomepizole)

Risk assessment tools

Identification of risk factors has been used to develop risk stratification tools

These tools are most useful where a potential nephrotoxic exposure occurs at a defined time (surgery, contrast exposure)

Identify patients that will benefit from close observation and renal protective strategies

Good negative predictive power but poor positive predictive power

Example: Risk for development of contrast-induced nephropathy (CIN) according to CIN risk score

Variables:

2 points for each of the following:

Creatinine clearance < 60ml/min

Urgent PCI

Intra-aortic balloon pump

1 point for each of the following:

Diabetes Mellitus

Congestive heart failure

Hypertension

Peripheral vascular disease

Contrast volume > 260 ml

Bartholomew et al. Am J Cardiol 93: 1515-9, 2004

Integrated structure-process framework for computer decision support

-Knowledge base

-Inference engine

-Communication

Chang, Rosner et al. Nature Rev Nephrol 7: 348-355 (2011)

Computer decision support systems in nephrology

Only one study has examined the impact of CDSS on the prevention of AKI

Demonstrated one of the greatest reductions in the rate of AKI seen in any intervention study

In this study, an alert was generated for a patient prescribed a potentially nephrotoxic medication when there was an increase in serum creatinine of >44.2 μmol/l (>0.5 mg/dl) from baseline after starting the medication.

This alert system resulted in a significant decrease in renal impairment in the group that received these alerts as compared with the group that did not receive alerts (relative risk 0.45, 95% CI 0.22–0.94).

Rind, D. M. et al. Effect of computer-based alerts on the treatment and outcomes of hospitalized

patients. Arch. Intern. Med. 154, 1511–1517 (1994).

Hydration as a preventative strategy

Hydration/Fluid Therapy Volume depletion is a clear

risk factor for ARF Clearly important in the

prevention of contrast nephropathy, pigment-induced ARF and prevention of drug-induced injury (amphotericin B, methotrexate, acyclovir)

Role in contrast nephropathy: 78 patients with CKD (Scr 1.6

mg/dl or CCl <60 ml/min) undergoing coronary angiography

0

10

20

30

40

50

Diabetic

Non-diabetic

% I

ncid

en

ce o

f A

RF

Saline Mannitol Furosemide

Solomon et. al. NEJM 331:1416-

1420, 1994

Sepsis and AKI: Management Issues

Sepsis: Can AKI be prevented?

No good predictive scoring system

Significant renal damage occurs very early and often before overt signs/symptoms of sepsis are seen

In the Rivers et al trial of early goal directed therapy (EGDT):

Presenting serum creatinine was 2.6 +/- 2.0 signifying that a large percentage of patients present already in AKI.

How can AKI in complex scenarios be prevented?

Pathogenesis- An example of an ICU patient

Ischemia Sepsis

Toxins

AKI

Drugs

Heme proteins

Contrast media

Hypoperfusion

Altered NO-ET

balance

Reperfusion

injury

Increased RVR

Systemic inflammation

LPS/endotoxin

Activated leukocytes

Activated monocytes

Cytokines

Complement activation

Coagulation activation

Spectrum of kidney injury

Prerenal Sublethal Injury Apoptosis Necrosis

Oliguric AKI due to sepsis- A crossroads

ENTRY POINT: SEPSIS

Early goal directed therapy

Fluid Challenge:

crystalloid/colloid

Vasopressors:

Norepinephrine/vasopressin Diuretics

Renal replacement

therapy

OLIGURIA

The imperative: maintain renal blood flow even if initial injury not due to ischemia?

Can AKI be

prevented?

What does oliguria represent?

Prerenal state

Reversible early injury

Irreversible injury

Renal Blood Flow in Sepsis

Brenner M, et al. Chest 1990; 98: 170-179

Renal blood in sepsis actually

increases and thus methods

targeted to increase RBF may

not be necessary

Early goal directed therapy (EGDT)

Protocol to reverse early hemodynamic perturbations- must occur early in the process- general consensus that acute and aggressive early resuscitation is important: Rivers et al New Engl J Med 345: 1368, 2001

Should be targeted to physiologic end-points:

Mean arterial pressure (MAP > 65 mm Hg)

Central venous pressure (CVP > 8-12 mm Hg)

Urine output ( > 0.5 ml/kg/hour)

Cardiac output

ScvO2 (> 70%)

EGDT and AKI?

In the Rivers trial: no data on cumulative fluid balance, urine output, diuretic therapy, and renal outcomes

Recent study from this group looked at biomarkers: TNF-α, caspase-3, IL-8, ICAM-1 and showed that early correction of hemodynamic derangements corrected some parameters that could impact on the development of AKI (Rivers et al Crit Care Med 35: 2016, 2007)

Need a study that addresses effects of EGDT on renal outcomes

Other factors that are likely critical in decreasing renal failure (but have not been well studied) include: early and appropriate antibiotic therapy.

A modified goal-directed protocol improves clinical outcomes…

Randomized 224 patients with established sepsis to a protocol using central venous pressure, mean arterial pressure, and urine output as therapeutic goals (similar to Rivers et al)

Reduced mortality (53.7 v. 71.6% p = 0.006)

Decreased ICU length of stay (14.3 v. 20.3 p = 0.003)

Decreased ventilator days (12.9 v. 18.8 p = 0.003)

Incidence of AKI fell from 55.2% to 38.9% (p = 0.015)

Lin et al. Shock 26: 551, 2006

After early resuscitation in the oliguric patient: Fluid management to prevent AKI

An obvious therapeutic option for those patients who remain oliguric is a fluid challenge: Problems:

Oliguria is not a necessarily an indication for volume expansion. May represent a stage of irreversible injury. Although added fluids may temporarily increase urine flow there is

no evidence that this improves renal outcomes Typical hemodynamic measures (CVP, PaOP) do not allow us to

predict volume responsiveness (more dynamic measures such as respiratory variation in systolic pressure are better).

Most importantly: liberal use of fluid therapy is associated with harm and a positive cumulative fluid balance has been shown in several studies to predict hospital mortality.

Need to be very cautious in continuing volume therapy unless using a dynamic measure and continually assessing the response to fluids.

Restrictive v. liberal fluid management in ARDS. ARDSNet FACCT Trial

The mean (±SE) cumulative fluid balance during the first seven days was –136±491 ml in the conservative-strategy group and 6992±502 ml in the liberal-strategy group (P<0.001).

Globally, no difference in mortality at 60 days

Improved lung function, increased ventilator free days, reduced ICU LOS, and no increase in rate of non-pulmonary organ failure.

TREND for reduced need for renal replacement therapy (10% restrictive v. 14% for liberal, p = 0.06) despite higher BUN and creatinine in the restrictive group.

NEJM 354: 2564, 2006

Cumulative daily fluid balance for days 1 through 7 following the onset of septic shock

Murphy C V et al. Chest 2009;136:102-109

Non-survivors

Survivors

Fluid Balance in AKI

Payen D et al. Crit Care 2008; 12: R74

Fluid Balance and Outcomes in AKI

Dialysis Pts.

Non-

Dialysis

Pts.

Bouchard J et al. Kidney Int 2008; 76: 422

Vasopressors: Is there a best option?

Maintaining renal perfusion (?) Most significant threats are systemic arterial hypotension

and increased intra-abdominal pressure.

To achieve adequate renal perfusion, often need pressors to maintain mean arterial pressure at 60-65 mm Hg (may need higher mean pressures in those patients with a history of hypertension or CKD who have impaired renal autoregulation).

Studies have shown no benefit of increasing MAP > 65 mm Hg (may not be true for those with long-standing hypertension)

Is there a preferred pressor for renal protection?

Di Giantomasso: Crit Care Med, Volume

31(10).October 2003.2509-2513

Effects of norepinephrine on renal and systemic hemodynamics in sepsis

Vasopressin?

Early small (24 subjects) trial demonstrated that vasopressin in septic shock was associated with improved urine output, increased creatinine clearance (unlike norepinephrine)

Patel BM et al. Anesthesiology 96: 576, 2002

VASST Trial: vasopressin and norepinephrine showed equivalence in all outcomes including need for renal replacement. Trend toward better survival in less severe septic patients receiving vasopressin.

Brunkhorst et al. N Engl J Med. 10:125-39, 2008.

Abdominal Compartment Syndrome

Renal Effects Increased intra-abdominal pressure leads to:

Compression of renal vein and parenchyma Increased renal vascular resistance Decreased renal blood flow and fall in glomerular filtration Oliguria and anuria

Occurs as IAP rises above 15-20 mm Hg (measured through bladder pressures)

Early therapy of moderately elevated IAP is with IVF May require decompressive surgery Recent study documents significant rise in IAP in acute

decompensated heart failure that correlated with changes in GFR (J Am Coll Cardiol 51: 300, 2008)

Shear and Rosner, Am J Nephrol 19:556-565

Diuretic use and AKI

Theoretically, very attractive Inhibits Na+/K+/2Cl- pump on luminal cell membrane

surface in medullary thick ascending loop of Henle and can reduce oxygen demands

Aids management of volume overload: Augments natriuresis and diuresis Helps maintain potassium and acid-base homeostasis Aids in ability to deliver maximal nutritional support

Survey data from intensivists and nephrologists: 50-70% of ICU patients receive loop diuretics Bagshaw et al. Contrib Nephrol 156: 236, 2007.

Many small studies that do not demonstrate benefit Two large observational studies with discrepant results

Diuretics, mortality and nonrecovery of renal function in acute renal failure

JAMA 288: 2547, 2002

All patients had nephrology consultation and received diuretics on/before the

day of consultation

Key point: If there is no

increase in urine output to

a diuretic, continuing the

diuretic may be harmful

Patients who do not respond

to diuretics with increased

urine output have the worse

outcome. If patients

responded, then there was

no difference in mortality

Uchino et al. studied a cohort

of 1743 ICU patients with AKI

and could not demonstrate a

significant impact of diuretic

use on mortality with odds-

ratio of 1.2 (NS)

Crit Care Med 32: 1669, 2003

Pharmacological Therapies

Multiple agents have been studied with little success

Currently, the only FDA approved therapy for the treatment of AKI is dialysis

Two recent studies have addressed the dosing of dialysis for critically ill patients and both demonstrated no benefit of more intensive dosing regimens (VA-ATN and RENAL trial)

In studies comparing CRRT and IHD in patients with AKI, there have been no studies demonstrating superiority of one modality over another

Individualized decision

Delivered CRRT Dose: Best Practice Window

Kellum and Ronco, Nature Revs Nephrol 2010

When should we begin RRT?

What specific criteria exist for beginning RRT in ICU patients?

Little agreement with regard to optimal timing of initiation of RRT

Majority of literature uses surrogate biochemical markers (BUN or creatinine) and demonstrates better outcomes with initiation prior to retention of uremic solutes (BUN < 70 mg/dL)

Other timing: duration of oliguria, timing from ICU admission, fluid volume status, electrolyte disarray, severe acidosis

Timing of RRT Initiation (< or > 2 days after ICU admission):

Effect on Outcome

Payen et al, Crit Care 2008

Fluid Balance:

Early +150 ml over ICU stay

Late +1500 ml over ICU stay

Timing of RRT Initiation: Effect on Outcome

Bagshaw et al, J Crit Care 2008

Timing of Initiation Crude Mortality (%) OR for Death

Early (< 2 days) 58.9 1.0

Delayed (2-5 days) 62.1 1.19

Late (> 5 days) 72.8 2.20*

*: Significantly greater than Early group

Timing of RRT Initiation: Meta-Analysis

Seabra et al, AJKD 2008

0

.2

.4

.6

.8

1

0 20 40 60 80 100

IRRT

CRRT

Days

Recovery from Dialysis Dependence:

BEST Kidney R

ecovery

fro

m d

ialy

sis

dependence

Uchino et al., Int J Artif Organs 2007

Note that the likelihood of recovering renal function after approximately 50 days is very low,

Data consistent with other RCTs:

CRRT associated with improved renal recovery

Renal Recovery after Post-Operative AKI Lin et al, Am J Surg 2010

Recovery of Renal Function

Strong suggestion from RENAL v. VA/ATN that CRRT improves the likelihood of renal recovery over IHD

May be an under recognized benefit of the use of CRRT

Fluid management: CRRT v. IHD

Several observational studies have shown a direct relationship between fluid accumulation and mortality in critically ill patients.

PICARD Study: Those with > 10% fluid accumulation had higher mortality and those

needing RRT who had significant fluid accumulation at the time of initiation had an OR of death of 2.07 v. those with less fluid accumulation

Fluid removal in IHD patients approximated 6-9L/week

Fluid removal in CRRT patients approximated > 20L/week

Neurotrauma: A unique benefit of CRRT

Goal to maintain cerebral perfusion and manage intracranial hypertension

CRRT:

Slower reduction in serum urea and minimizes changes in serum osmolality

Ability to maintain high-normal serum sodium

Regional citrate anticoagulation

Fletcher JJ et al. Neurocrit Care 2009; 11: 101-5

Summary

The incidence of AKI is increasing

AKI is associated with increased mortality, morbidity and risk for progressive CKD

Biomarkers are needed for rapid, early diagnosis of AKI and to allow early therapeutic intervention

Preventative strategies should be employed wherever possible

The patient with sepsis and AKI is especially challenging and fluid/volume management is critical

Data supports early nephrology consultation and institution of renal replacement therapies

CRRT may offer some advantages

Novel therapeutics are needed to treat AKI